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Chi, Jen-Tsan Ashley

Positions:

Associate Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Associate Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Assistant Professor of Medicine

Medicine, Rheumatology and Immunology
School of Medicine

Assistant Professor in Radiation Oncology

Radiation Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1991

M.D. — National Taiwan University

Ph.D. 2000

Ph.D. — Stanford University

Postdoctoral Research, Biochemistry

Stanford University

News:

Grants:

Targeting the Hippo pathway in Ras-driven rhabdomyosarcoma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
V Foundation for Cancer Research
Role
Collaborator
Start Date
November 01, 2016
End Date
October 31, 2019

Human Stringent Response as Novel Therapeutic Approaches for Breast Cancers

Administered By
Molecular Genetics and Microbiology
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
September 30, 2015
End Date
September 29, 2018

Duke KURe Program

Administered By
Obstetrics and Gynecology, Urogynecology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 01, 2013
End Date
July 31, 2018

Development Of Prognostic Platelet RNA Biomarkers To Tailor Antiplatelet Therapy

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 05, 2013
End Date
May 31, 2018

Targeting the synthetic essential kinases of breast cancers

Administered By
Molecular Genetics and Microbiology
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
April 15, 2015
End Date
April 14, 2018

Immune regulated amino acid pathways in Alzheimer's Disease

Administered By
Neurology, Behavioral Neurology
AwardedBy
National Institutes of Health
Role
Collaborating Investigator
Start Date
September 30, 2016
End Date
August 31, 2017

Small RNA transcriptome as novel approaches to detect autologous blood transfusion

Administered By
Molecular Genetics and Microbiology
AwardedBy
World Anti-Doping Agency
Role
Principal Investigator
Start Date
August 23, 2016
End Date
August 22, 2017

Gene expression programs of lactic acidosis in human cancers

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 02, 2007
End Date
April 30, 2017

Duke-UNC Clinical Hematology and Transfusion Research Career Development Program

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 28, 2006
End Date
April 30, 2017

Functional Genomic Screens of Tumor Recurrence in Ovarian Cancer

Administered By
Molecular Genetics and Microbiology
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
August 22, 2014
End Date
February 21, 2017

Bioinformatics and Computational Biology Training Program

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2005
End Date
June 30, 2016

Oncogenic Gene Regulatory Networks

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2004
End Date
December 31, 2015

Genetic elements of cancer cell survival in tumor microenvironment stresses

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2013
End Date
December 04, 2015

Detecting autologous blood doping through the analysis of erythrocyte transcriptome

Administered By
Molecular Genetics and Microbiology
AwardedBy
World Anti-Doping Agency
Role
Principal Investigator
Start Date
September 12, 2014
End Date
September 11, 2015

Instrumentation for Quantitative Phosphoproteomics and Acetylomics

Administered By
Duke Center for Genomic and Computational Biology
AwardedBy
National Institutes of Health
Role
Major User
Start Date
May 15, 2014
End Date
May 14, 2015

InCh Microscope: Compact and Portable Quantitative Phase Microscope for Label-Free Morphological Diagnosis of Blood Samp

Administered By
Biomedical Engineering
AwardedBy
M2 Photonics Innovations
Role
Co Investigator
Start Date
January 01, 2014
End Date
December 31, 2014

Resveratrol, Carbohydrate Restriction and Prostate Cancer Progression

Administered By
Surgery, Urology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 15, 2008
End Date
July 31, 2014

Molecular Modeling of Pediatric Skeletal Muscle Tumors

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
January 01, 2009
End Date
November 30, 2013

Illumina Hi-Seq 2000 Sequencing System

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Major User
Start Date
May 07, 2012
End Date
May 06, 2013

Phase I Clinical Trial Describing the Pharmacogenomics of Aspirin

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 30, 2009
End Date
August 31, 2012

Gene expression programs of lactic acidosis in human cancers

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 02, 2007
End Date
April 30, 2012

The Genomic Analysis of Erythrocyte microRNA in Sickle Cell Diseases

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2008
End Date
April 30, 2011
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Awards:

Member of American Society of Clinical Investigation. American Society of Clinical Investigation.

Type
National
Awarded By
American Society of Clinical Investigation
Date
January 01, 2011

Investigators in Pathogenesis of Infectious Diseases. Burroughs Wellcome Fund.

Type
National
Awarded By
Burroughs Wellcome Fund
Date
January 01, 2009

Publications:

Hemoglobin consumption by P. falciparum in individual erythrocytes imaged via quantitative phase spectroscopy.

Plasmodium falciparum infection causes structural and biochemical changes in red blood cells (RBCs). To quantify these changes, we apply a novel optical technique, quantitative phase spectroscopy (QPS) to characterize individual red blood cells (RBCs) during the intraerythrocytic life cycle of P. falciparum. QPS captures hyperspectral holograms of individual RBCs to measure spectroscopic changes across the visible wavelength range (475-700 nm), providing complex information, i.e. amplitude and phase, about the light field which has interacted with the cell. The complex field provides complimentary information on hemoglobin content and cell mass, which are both found to dramatically change upon infection by P. falciparum. Hb content progressively decreases with parasite life cycle, with an average 72.2% reduction observed for RBCs infected by schizont-stage P. falciparum compared to uninfected cells. Infection also resulted in a 33.1% reduction in RBC's optical volume, a measure of the cells' non-aqueous components. Notably, optical volume is only partially correlated with hemoglobin content, suggesting that changes in other dry mass components such as parasite mass may also be assessed using this technique. The unique ability of QPS to discriminate individual healthy and infected cells using spectroscopic changes indicates that the approach can be used to detect disease.

Authors
Rinehart, MT; Park, HS; Walzer, KA; Chi, J-TA; Wax, A
MLA Citation
Rinehart, MT, Park, HS, Walzer, KA, Chi, J-TA, and Wax, A. "Hemoglobin consumption by P. falciparum in individual erythrocytes imaged via quantitative phase spectroscopy." Scientific reports 6 (April 18, 2016): 24461-.
PMID
27087557
Source
epmc
Published In
Scientific Reports
Volume
6
Publish Date
2016
Start Page
24461
DOI
10.1038/srep24461

Secreted Frizzled-Related Protein 3 (SFRP3) Is Required for Tumorigenesis of PAX3-FOXO1-Positive Alveolar Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma associated with the skeletal muscle lineage. Of the two predominant subtypes, known as embryonal (eRMS) and alveolar (aRMS), aRMS has the poorer prognosis, with a five-year survival rate of <50%. The majority of aRMS tumors express the fusion protein PAX3-FOXO1. As PAX3-FOXO1 has proven chemically intractable, this study aims to identify targetable proteins that are downstream from or cooperate with PAX3-FOXO1 to support tumorigenesis.Microarray analysis of the transcriptomes of human skeletal muscle myoblasts expressing PAX3-FOXO1 revealed alteration of several Wnt pathway gene members, including secreted frizzled related protein 3 (SFRP3), a secreted Wnt pathway inhibitor. Loss-of-function using shRNAs against SFRP3 was used to interrogate the role of SFRP3 in human aRMS cell lines in vitro and conditional murine xenograft systems in vivo. The combination of SFRP3 genetic suppression and the chemotherapeutic agent vincristine was also examined.In vitro, suppression of SFRP3 inhibited aRMS cell growth, reduced proliferation accompanied by a G1 arrest and induction of p21, and induced apoptosis. In vivo, doxycycline-inducible suppression of SFRP3 reduced aRMS tumor growth and weight by more than three-fold, in addition to increasing myogenic differentiation and β-catenin signaling. The combination of SFRP3 suppression and vincristine was more effective at reducing aRMS cell growth in vitro than either treatment alone, and ablated tumorigenesis in vivo.SFRP3 is necessary for the growth of human aRMS cells both in vitro and in vivo and is a promising new target for investigation in aRMS.

Authors
Kephart, JJG; Tiller, RGJ; Crose, LES; Slemmons, KK; Chen, P-H; Hinson, AR; Bentley, RC; Chi, J-TA; Linardic, CM
MLA Citation
Kephart, JJG, Tiller, RGJ, Crose, LES, Slemmons, KK, Chen, P-H, Hinson, AR, Bentley, RC, Chi, J-TA, and Linardic, CM. "Secreted Frizzled-Related Protein 3 (SFRP3) Is Required for Tumorigenesis of PAX3-FOXO1-Positive Alveolar Rhabdomyosarcoma." Clinical cancer research : an official journal of the American Association for Cancer Research 21.21 (November 2015): 4868-4880.
PMID
26071485
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
21
Publish Date
2015
Start Page
4868
End Page
4880
DOI
10.1158/1078-0432.ccr-14-1797

FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target.

Although a standardized approach to radiotherapy has been used to treat breast cancer, regardless of subtype (e.g., luminal, basal), recent clinical data suggest that radiation response may vary significantly among subtypes. We hypothesized that this clinical variability may be due, in part, to differences in cellular radiation response. In this study, we utilized RNA samples for microarray analysis from two sources: 1. Paired pre- and postirradiation breast tumor tissue from 32 early-stage breast cancer patients treated in our unique preoperative radiation Phase I trial; and 2. Sixteen biologically diverse breast tumor cell lines exposed to 0 and 5 Gy irradiation. The transcriptome response to radiation exposure was derived by comparing gene expression in samples before and after irradiation. Genes with the highest coefficient of variation were selected for further evaluation and validated at the RNA and protein level. Gene editing and agonistic antibody treatment were performed to assess the impact of gene modulation on radiation response. Gene expression in our cohort of luminal breast cancer patients was distinctly different before and after irradiation. Further, two distinct patterns of gene expression were observed in our biologically diverse group of breast cancer cell lines pre- versus postirradiation. Cell lines that showed significant change after irradiation were largely luminal subtype, while gene expression in the basal and HER2+ cell lines was minimally impacted. The 100 genes with the most significant response to radiation in patients were identified and analyzed for differential patterns of expression in the radiation-responsive versus nonresponsive cell lines. Fourteen genes were identified as significant, including FAS, a member of the tumor necrosis factor receptor family known to play a critical role in programed cell death. Modulation of FAS in breast cancer cell lines altered radiation response phenotype and enhanced radiation sensitivity in radioresistant basal cell lines. Our findings suggest that cell-type-specific, radiation-induced FAS contributes to subtype-specific breast cancer radiation response and that activation of FAS pathways may be exploited for biologically tailored radiotherapy.

Authors
Horton, JK; Siamakpour-Reihani, S; Lee, C-T; Zhou, Y; Chen, W; Geradts, J; Fels, DR; Hoang, P; Ashcraft, KA; Groth, J; Kung, H-N; Dewhirst, MW; Chi, J-TA
MLA Citation
Horton, JK, Siamakpour-Reihani, S, Lee, C-T, Zhou, Y, Chen, W, Geradts, J, Fels, DR, Hoang, P, Ashcraft, KA, Groth, J, Kung, H-N, Dewhirst, MW, and Chi, J-TA. "FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target." Radiation research 184.5 (November 2015): 456-469.
PMID
26488758
Source
epmc
Published In
Radiation Research
Volume
184
Issue
5
Publish Date
2015
Start Page
456
End Page
469
DOI
10.1667/rr14089.1

ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate.

In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, the loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased under hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4, likely via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that the ACC1/ACLY-α-ketoglutarate-ETV4 axis is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future.

Authors
Keenan, MM; Liu, B; Tang, X; Wu, J; Cyr, D; Stevens, RD; Ilkayeva, O; Huang, Z; Tollini, LA; Murphy, SK; Lucas, J; Muoio, DM; Kim, SY; Chi, J-T
MLA Citation
Keenan, MM, Liu, B, Tang, X, Wu, J, Cyr, D, Stevens, RD, Ilkayeva, O, Huang, Z, Tollini, LA, Murphy, SK, Lucas, J, Muoio, DM, Kim, SY, and Chi, J-T. "ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate." PLoS genetics 11.10 (October 9, 2015): e1005599-.
Website
http://hdl.handle.net/10161/13614
PMID
26452058
Source
epmc
Published In
PLoS genetics
Volume
11
Issue
10
Publish Date
2015
Start Page
e1005599
DOI
10.1371/journal.pgen.1005599

Synthesis and Biological Evaluation of Manassantin Analogues for Hypoxia-Inducible Factor 1α Inhibition.

To cope with hypoxia, tumor cells have developed a number of adaptive mechanisms mediated by hypoxia-inducible factor 1 (HIF-1) to promote angiogenesis and cell survival. Due to significant roles of HIF-1 in the initiation, progression, metastasis, and resistance to treatment of most solid tumors, a considerable amount of effort has been made to identify HIF-1 inhibitors for treatment of cancer. Isolated from Saururus cernuus, manassantins A (1) and B (2) are potent inhibitors of HIF-1 activity. To define the structural requirements of manassantins for HIF-1 inhibition, we prepared and evaluated a series of manassantin analogues. Our SAR studies examined key regions of manassantin's structure in order to understand the impact of these regions on biological activity and to define modifications that can lead to improved performance and drug-like properties. Our efforts identified several manassantin analogues with reduced structural complexity as potential lead compounds for further development. Analogues MA04, MA07, and MA11 down-regulated hypoxia-induced expression of the HIF-1α protein and reduced the levels of HIF-1 target genes, including cyclin-dependent kinase 6 (Cdk6) and vascular endothelial growth factor (VEGF). These findings provide an important framework to design potent and selective HIF-1α inhibitors, which is necessary to aid translation of manassantin-derived natural products to the clinic as novel therapeutics for cancers.

Authors
Kwon, D-Y; Lee, HE; Weitzel, DH; Park, K; Lee, SH; Lee, C-T; Stephenson, TN; Park, H; Fitzgerald, MC; Chi, J-T; Mook, RA; Dewhirst, MW; Lee, YM; Hong, J
MLA Citation
Kwon, D-Y, Lee, HE, Weitzel, DH, Park, K, Lee, SH, Lee, C-T, Stephenson, TN, Park, H, Fitzgerald, MC, Chi, J-T, Mook, RA, Dewhirst, MW, Lee, YM, and Hong, J. "Synthesis and Biological Evaluation of Manassantin Analogues for Hypoxia-Inducible Factor 1α Inhibition." Journal of medicinal chemistry 58.19 (October 2015): 7659-7671.
PMID
26394152
Source
epmc
Published In
Journal of Medicinal Chemistry
Volume
58
Issue
19
Publish Date
2015
Start Page
7659
End Page
7671
DOI
10.1021/acs.jmedchem.5b01220

A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models.

Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumour-specific uptake and therapeutic potential. To this end, here we conjugated paclitaxel (PTX) to recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into ∼60 nm near-monodisperse nanoparticles that increased the systemic exposure of PTX by sevenfold compared with free drug and twofold compared with the Food and Drug Administration-approved taxane nanoformulation (Abraxane). The tumour uptake of the CP-PTX nanoparticle was fivefold greater than free drug and twofold greater than Abraxane. In a murine cancer model of human triple-negative breast cancer and prostate cancer, CP-PTX induced near-complete tumour regression after a single dose in both tumour models, whereas at the same dose, no mice treated with Abraxane survived for >80 days (breast) and 60 days (prostate), respectively. These results show that a molecularly engineered nanoparticle with precisely engineered design features outperforms Abraxane, the current gold standard for PTX delivery.

Authors
Bhattacharyya, J; Bellucci, JJ; Weitzhandler, I; McDaniel, JR; Spasojevic, I; Li, X; Lin, C-C; Chi, J-TA; Chilkoti, A
MLA Citation
Bhattacharyya, J, Bellucci, JJ, Weitzhandler, I, McDaniel, JR, Spasojevic, I, Li, X, Lin, C-C, Chi, J-TA, and Chilkoti, A. "A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models." Nature communications 6 (August 4, 2015): 7939-.
PMID
26239362
Source
epmc
Published In
Nature Communications
Volume
6
Publish Date
2015
Start Page
7939
DOI
10.1038/ncomms8939

Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers.

Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response.Women aged ≥55 years with clinically node-negative, estrogen receptor-positive, and/or progesterone receptor-positive HER2-, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed.No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation.Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to challenge the current treatment paradigm and provide a path forward to identify radiation response biomarkers.

Authors
Horton, JK; Blitzblau, RC; Yoo, S; Geradts, J; Chang, Z; Baker, JA; Georgiade, GS; Chen, W; Siamakpour-Reihani, S; Wang, C; Broadwater, G; Groth, J; Palta, M; Dewhirst, M; Barry, WT; Duffy, EA; Chi, J-TA; Hwang, ES
MLA Citation
Horton, JK, Blitzblau, RC, Yoo, S, Geradts, J, Chang, Z, Baker, JA, Georgiade, GS, Chen, W, Siamakpour-Reihani, S, Wang, C, Broadwater, G, Groth, J, Palta, M, Dewhirst, M, Barry, WT, Duffy, EA, Chi, J-TA, and Hwang, ES. "Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers." International journal of radiation oncology, biology, physics 92.4 (July 2015): 846-855.
PMID
26104938
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
92
Issue
4
Publish Date
2015
Start Page
846
End Page
855
DOI
10.1016/j.ijrobp.2015.03.007

Suppression of PGC-1α Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma.

Long believed to be a byproduct of malignant transformation, reprogramming of cellular metabolism is now recognized as a driving force in tumorigenesis. In clear cell renal cell carcinoma (ccRCC), frequent activation of HIF signaling induces a metabolic switch that promotes tumorigenesis. Here, we demonstrate that PGC-1α, a central regulator of energy metabolism, is suppressed in VHL-deficient ccRCC by a HIF/Dec1-dependent mechanism. In VHL wild-type cells, PGC-1α suppression leads to decreased expression of the mitochondrial transcription factor Tfam and impaired mitochondrial respiration. Conversely, PGC-1α expression in VHL-deficient cells restores mitochondrial function and induces oxidative stress. ccRCC cells expressing PGC-1α exhibit impaired tumor growth and enhanced sensitivity to cytotoxic therapies. In patients, low levels of PGC-1α expression are associated with poor outcome. These studies demonstrate that suppression of PGC-1α recapitulates key metabolic phenotypes of ccRCC and highlight the potential of targeting PGC-1α expression as a therapeutic modality for the treatment of ccRCC.

Authors
LaGory, EL; Wu, C; Taniguchi, CM; Ding, C-KC; Chi, J-T; von Eyben, R; Scott, DA; Richardson, AD; Giaccia, AJ
MLA Citation
LaGory, EL, Wu, C, Taniguchi, CM, Ding, C-KC, Chi, J-T, von Eyben, R, Scott, DA, Richardson, AD, and Giaccia, AJ. "Suppression of PGC-1α Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma." Cell reports 12.1 (July 2015): 116-127.
PMID
26119730
Source
epmc
Published In
Cell Reports
Volume
12
Issue
1
Publish Date
2015
Start Page
116
End Page
127
DOI
10.1016/j.celrep.2015.06.006

Comprehensive profiling of amino acid response uncovers unique methionine-deprived response dependent on intact creatine biosynthesis.

Besides being building blocks for protein synthesis, amino acids serve a wide variety of cellular functions, including acting as metabolic intermediates for ATP generation and for redox homeostasis. Upon amino acid deprivation, free uncharged tRNAs trigger GCN2-ATF4 to mediate the well-characterized transcriptional amino acid response (AAR). However, it is not clear whether the deprivation of different individual amino acids triggers identical or distinct AARs. Here, we characterized the global transcriptional response upon deprivation of one amino acid at a time. With the exception of glycine, which was not required for the proliferation of MCF7 cells, we found that the deprivation of most amino acids triggered a shared transcriptional response that included the activation of ATF4, p53 and TXNIP. However, there was also significant heterogeneity among different individual AARs. The most dramatic transcriptional response was triggered by methionine deprivation, which activated an extensive and unique response in different cell types. We uncovered that the specific methionine-deprived transcriptional response required creatine biosynthesis. This dependency on creatine biosynthesis was caused by the consumption of S-Adenosyl-L-methionine (SAM) during creatine biosynthesis that helps to deplete SAM under methionine deprivation and reduces histone methylations. As such, the simultaneous deprivation of methionine and sources of creatine biosynthesis (either arginine or glycine) abolished the reduction of histone methylation and the methionine-specific transcriptional response. Arginine-derived ornithine was also required for the complete induction of the methionine-deprived specific gene response. Collectively, our data identify a previously unknown set of heterogeneous amino acid responses and reveal a distinct methionine-deprived transcriptional response that results from the crosstalk of arginine, glycine and methionine metabolism via arginine/glycine-dependent creatine biosynthesis.

Authors
Tang, X; Keenan, MM; Wu, J; Lin, C-A; Dubois, L; Thompson, JW; Freedland, SJ; Murphy, SK; Chi, J-T
MLA Citation
Tang, X, Keenan, MM, Wu, J, Lin, C-A, Dubois, L, Thompson, JW, Freedland, SJ, Murphy, SK, and Chi, J-T. "Comprehensive profiling of amino acid response uncovers unique methionine-deprived response dependent on intact creatine biosynthesis." PLoS genetics 11.4 (April 7, 2015): e1005158-.
PMID
25849282
Source
epmc
Published In
PLoS genetics
Volume
11
Issue
4
Publish Date
2015
Start Page
e1005158
DOI
10.1371/journal.pgen.1005158

Whole blood gene expression profiles distinguish clinical phenotypes of venous thromboembolism.

Recurrent venous thromboembolism (VTE) occurs infrequently following a provoked event but occurs in up to 30% of individuals following an initial unprovoked event. There is limited understanding of the biological mechanisms that predispose patients to recurrent VTE.To identify whole blood gene expression profiles that distinguished patients with clinically distinct patterns of VTE.We studied 107 patients with VTE separated into 3 groups: (1) 'low-risk' patients had one or more provoked VTE; (2) 'moderate-risk' patients had a single unprovoked VTE; (3) 'high-risk' patients had ≥2 unprovoked VTE. Each patient group was also compared to twenty-five individuals with no personal history of VTE. Total RNA from whole blood was isolated and hybridized to Illumina HT-12V4 Beadchips to assay whole genome expression.Using class prediction analysis, we distinguished high-risk patients from low-risk patients and healthy controls with good receiver operating curve characteristics (AUC=0.81 and 0.84, respectively). We also distinguished moderate-risk individuals and low-risk individuals from healthy controls with AUC's of 0.69 and 0.80, respectively. Using differential expression analysis, we identified several genes previously implicated in thrombotic disorders by genetic analyses, including SELP, KLKB1, ANXA5, and CD46. Protein levels for several of the identified genes were not significantly different between the different groups.Gene expression profiles are capable of distinguishing patients with different clinical presentations of VTE, and genes relevant to VTE risk are frequently differentially expressed in these comparisons.

Authors
Lewis, DA; Suchindran, S; Beckman, MG; Hooper, WC; Grant, AM; Heit, JA; Manco-Johnson, M; Moll, S; Philipp, CS; Kenney, K; De Staercke, C; Pyle, ME; Chi, J-T; Ortel, TL
MLA Citation
Lewis, DA, Suchindran, S, Beckman, MG, Hooper, WC, Grant, AM, Heit, JA, Manco-Johnson, M, Moll, S, Philipp, CS, Kenney, K, De Staercke, C, Pyle, ME, Chi, J-T, and Ortel, TL. "Whole blood gene expression profiles distinguish clinical phenotypes of venous thromboembolism." Thrombosis research 135.4 (April 2015): 659-665.
PMID
25684211
Source
epmc
Published In
Thrombosis Research
Volume
135
Issue
4
Publish Date
2015
Start Page
659
End Page
665
DOI
10.1016/j.thromres.2015.02.003

Alternative fuels for cancer cells.

Tumor metabolism is significantly altered to support the various metabolic needs of tumor cells. The most prominent change is the increased tumor glycolysis that leads to increased glucose uptake and utilization. However, it has become obvious that many non-glucose nutrients, such as amino acids, lactate, acetate, and macromolecules, can serve as alternative fuels for cancer cells. This knowledge reveals an unexpected flexibility and evolutionarily conserved model in which cancer cells uptake nutrients from their external environment to fulfill their necessary energetic needs. Tumor cells may have evolved the ability to utilize different carbon sources because of the limited supply of nutrients in their microenvironment, which can be driven by oncogenic mutations or tumor microenvironmental stresses. In certain cases, these factors permanently alter the tumor cells' metabolism, causing certain nutrients to become indispensable and thus creating opportunities for therapeutic intervention to eradicate tumors by their metabolic vulnerabilities.

Authors
Keenan, MM; Chi, J-T
MLA Citation
Keenan, MM, and Chi, J-T. "Alternative fuels for cancer cells." Cancer journal (Sudbury, Mass.) 21.2 (March 2015): 49-55. (Review)
PMID
25815843
Source
epmc
Published In
Cancer Journal
Volume
21
Issue
2
Publish Date
2015
Start Page
49
End Page
55
DOI
10.1097/ppo.0000000000000104

Whole blood gene expression profiles distinguish clinical phenotypes of venous thromboembolism

© 2015 Elsevier Ltd.Introduction Recurrent venous thromboembolism (VTE) occurs infrequently following a provoked event but occurs in up to 30% of individuals following an initial unprovoked event. There is limited understanding of the biological mechanisms that predispose patients to recurrent VTE. Objectives To identify whole blood gene expression profiles that distinguished patients with clinically distinct patterns of VTE. Patients/Methods We studied 107 patients with VTE separated into 3 groups: (1) 'low-risk' patients had one or more provoked VTE; (2) 'moderate-risk' patients had a single unprovoked VTE; (3) 'high-risk' patients had 2 unprovoked VTE. Each patient group was also compared to twenty-five individuals with no personal history of VTE. Total RNA from whole blood was isolated and hybridized to Illumina HT-12 V4 Beadchips to assay whole genome expression. Results Using class prediction analysis, we distinguished high-risk patients from low-risk patients and healthy controls with good receiver operating curve characteristics (AUC = 0.81 and 0.84, respectively). We also distinguished moderate-risk individuals and low-risk individuals from healthy controls with AUC's of 0.69 and 0.80, respectively. Using differential expression analysis, we identified several genes previously implicated in thrombotic disorders by genetic analyses, including SELP, KLKB1, ANXA5, and CD46. Protein levels for several of the identified genes were not significantly different between the different groups. Conclusion Gene expression profiles are capable of distinguishing patients with different clinical presentations of VTE, and genes relevant to VTE risk are frequently differentially expressed in these comparisons.

Authors
Lewis, DA; Suchindran, S; Beckman, MG; Hooper, WC; Grant, AM; Heit, JA; Manco-Johnson, M; Moll, S; Philipp, CS; Kenney, K; De Staercke, C; Pyle, ME; Chi, JT; Ortel, TL
MLA Citation
Lewis, DA, Suchindran, S, Beckman, MG, Hooper, WC, Grant, AM, Heit, JA, Manco-Johnson, M, Moll, S, Philipp, CS, Kenney, K, De Staercke, C, Pyle, ME, Chi, JT, and Ortel, TL. "Whole blood gene expression profiles distinguish clinical phenotypes of venous thromboembolism." Thrombosis Research 135.4 (January 1, 2015): 659-665.
Source
scopus
Published In
Thrombosis Research
Volume
135
Issue
4
Publish Date
2015
Start Page
659
End Page
665
DOI
10.1016/j.thromres.2015.02.003

The role of glutamine synthetase in the glutamine independence in mammary tissue

© Springer Science+Business Media New York 2015.Glutamine addiction of cancer cells is thought to be an attractive way to prevent cancer growth and spreading. Although some regulatory factors of glutamine consumption are known, the actual cell-type specific regulatory mechanism hasn’t been explored yet. In breast tumors, there are two types of tumor cells that may be malignantly transformed from different cellular origins with dramatically different gene expression. We found distinct glutamine requirement in these two types of cells: luminal epithelial cells, as well as their corresponding transformed tumor cells, are more independent to extracellular glutamine than basal cells. This luminal-specific glutamine independent is regulated by its specific expression of glutamine synthetase, which can produce glutamine by combing glutamate and amine group. In response to glutamine deprivation, the expression of glutamine synthetase in luminal cells allow them to produce and export glutamine to the extracellular space to support the survival of glutamine addicted basal cells in a mechanism of metabolic symbiosis. By these observations, the glutamine deprivation therapy should be performed more efficiently with the help of glutamine synthetase inhibition.

Authors
Kung, HN; Chi, JT
MLA Citation
Kung, HN, and Chi, JT. "The role of glutamine synthetase in the glutamine independence in mammary tissue." (January 1, 2015): 87-97. (Chapter)
Source
scopus
Publish Date
2015
Start Page
87
End Page
97
DOI
10.1007/978-1-4939-1932-1_7

E2F1-Mediated Induction of NFYB Attenuates Apoptosis via Joint Regulation of a Pro-Survival Transcriptional Program.

The E2F1 transcription factor regulates cell proliferation and apoptosis through the control of a considerable variety of target genes. Previous work has detailed the role of other transcription factors in mediating the specificity of E2F function. Here we identify the NF-YB transcription factor as a novel direct E2F1 target. Genome-wide expression analysis of the effects of NFYB knockdown on E2F1-mediated transcription identified a large group of genes that are co-regulated by E2F1 and NFYB. We also provide evidence that knockdown of NFYB enhances E2F1-induced apoptosis, suggesting a pro-survival function of the NFYB/E2F1 joint transcriptional program. Bioinformatic analysis suggests that deregulation of these NFY-dependent E2F1 target genes might play a role in sarcomagenesis as well as drug resistance.

Authors
Jiang, X; Nevins, JR; Shats, I; Chi, J-T
MLA Citation
Jiang, X, Nevins, JR, Shats, I, and Chi, J-T. "E2F1-Mediated Induction of NFYB Attenuates Apoptosis via Joint Regulation of a Pro-Survival Transcriptional Program." PloS one 10.6 (January 2015): e0127951-.
PMID
26039627
Source
epmc
Published In
PloS one
Volume
10
Issue
6
Publish Date
2015
Start Page
e0127951
DOI
10.1371/journal.pone.0127951

Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis.

PICALM (Phosphatidyl Inositol Clathrin Assembly Lymphoid Myeloid protein) is a ubiquitously expressed protein that plays a role in clathrin-mediated endocytosis. PICALM also affects the internalization and trafficking of SNAREs and modulates macroautophagy. Chromosomal translocations that result in the fusion of PICALM to heterologous proteins cause leukemias, and genome-wide association studies have linked PICALM Single Nucleotide Polymorphisms (SNPs) to Alzheimer's disease. To obtain insight into the biological role of PICALM, we performed gene expression studies of PICALM-deficient and PICALM-expressing cells. Pathway analysis demonstrated that PICALM expression influences the expression of genes that encode proteins involved in cholesterol biosynthesis and lipoprotein uptake. Gas Chromatography-Mass Spectrometry (GC-MS) studies indicated that loss of PICALM increases cellular cholesterol pool size. Isotopic labeling studies revealed that loss of PICALM alters increased net scavenging of cholesterol. Flow cytometry analyses confirmed that internalization of the LDL receptor is enhanced in PICALM-deficient cells as a result of higher levels of LDLR expression. These findings suggest that PICALM is required for cellular cholesterol homeostasis and point to a novel mechanism by which PICALM alterations may contribute to disease.

Authors
Mercer, JL; Argus, JP; Crabtree, DM; Keenan, MM; Wilks, MQ; Chi, J-TA; Bensinger, SJ; Lavau, CP; Wechsler, DS
MLA Citation
Mercer, JL, Argus, JP, Crabtree, DM, Keenan, MM, Wilks, MQ, Chi, J-TA, Bensinger, SJ, Lavau, CP, and Wechsler, DS. "Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis." PloS one 10.6 (January 2015): e0129776-.
PMID
26075887
Source
epmc
Published In
PloS one
Volume
10
Issue
6
Publish Date
2015
Start Page
e0129776
DOI
10.1371/journal.pone.0129776

A comprehensive joint analysis of the long and short RNA transcriptomes of human erythrocytes.

Human erythrocytes are terminally differentiated, anucleate cells long thought to lack RNAs. However, previous studies have shown the persistence of many small-sized RNAs in erythrocytes. To comprehensively define the erythrocyte transcriptome, we used high-throughput sequencing to identify both short (18-24 nt) and long (>200 nt) RNAs in mature erythrocytes.Analysis of the short RNA transcriptome with miRDeep identified 287 known and 72 putative novel microRNAs. Unexpectedly, we also uncover an extensive repertoire of long erythrocyte RNAs that encode many proteins critical for erythrocyte differentiation and function. Additionally, the erythrocyte long RNA transcriptome is significantly enriched in the erythroid progenitor transcriptome. Joint analysis of both short and long RNAs identified several loci with co-expression of both microRNAs and long RNAs spanning microRNA precursor regions. Within the miR-144/451 locus previously implicated in erythroid development, we observed unique co-expression of several primate-specific noncoding RNAs, including a lncRNA, and miR-4732-5p/-3p. We show that miR-4732-3p targets both SMAD2 and SMAD4, two critical components of the TGF-β pathway implicated in erythropoiesis. Furthermore, miR-4732-3p represses SMAD2/4-dependent TGF-β signaling, thereby promoting cell proliferation during erythroid differentiation.Our study presents the most extensive profiling of erythrocyte RNAs to date, and describes primate-specific interactions between the key modulator miR-4732-3p and TGF-β signaling during human erythropoiesis.

Authors
Doss, JF; Corcoran, DL; Jima, DD; Telen, MJ; Dave, SS; Chi, J-T
MLA Citation
Doss, JF, Corcoran, DL, Jima, DD, Telen, MJ, Dave, SS, and Chi, J-T. "A comprehensive joint analysis of the long and short RNA transcriptomes of human erythrocytes." BMC genomics 16 (January 2015): 952-.
PMID
26573221
Source
epmc
Published In
BMC Genomics
Volume
16
Publish Date
2015
Start Page
952
DOI
10.1186/s12864-015-2156-2

Utilization of the Eμ-Myc mouse to model heterogeneity of therapeutic response.

Human aggressive B-cell non-Hodgkin lymphomas (NHL) encompass the continuum between Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL), and display considerable clinical and biologic heterogeneity, most notably related to therapy response. We previously showed that lymphomas arising in the Eμ-Myc transgenic mouse are heterogeneous, mirroring genomic differences between Burkitt lymphoma and DLBCL. Given clinical heterogeneity in NHL and the need to develop strategies to match therapeutics with discrete forms of disease, we investigated the extent to which genomic variation in the Eμ-Myc model predicts response to therapy. We used genomic analyses to classify Eμ-Myc lymphomas, link Eμ-Myc lymphomas with NHL subtypes, and identify lymphomas with predicted resistance to conventional and NF-κB-targeted therapies. Experimental evaluation of these predictions links genomic profiles with distinct outcomes to conventional and targeted therapies in the Eμ-Myc model, and establishes a framework to test novel targeted therapies or combination therapies in specific genomically defined lymphoma subgroups. In turn, this will rationally inform the design of new treatment options for aggressive human NHL.

Authors
Rempel, RE; Jiang, X; Fullerton, P; Tan, TZ; Ye, J; Lau, JA; Mori, S; Chi, J-T; Nevins, JR; Friedman, DR
MLA Citation
Rempel, RE, Jiang, X, Fullerton, P, Tan, TZ, Ye, J, Lau, JA, Mori, S, Chi, J-T, Nevins, JR, and Friedman, DR. "Utilization of the Eμ-Myc mouse to model heterogeneity of therapeutic response." Molecular cancer therapeutics 13.12 (December 2014): 3219-3229.
PMID
25349303
Source
epmc
Published In
Molecular cancer therapeutics
Volume
13
Issue
12
Publish Date
2014
Start Page
3219
End Page
3229
DOI
10.1158/1535-7163.mct-13-0044

An unexpected alliance between stress responses to drive oncogenesis

Authors
Keenan, MM; Ding, C-KC; Chi, J-T
MLA Citation
Keenan, MM, Ding, C-KC, and Chi, J-T. "An unexpected alliance between stress responses to drive oncogenesis." Breast Cancer Research 16.6 (December 2014).
Source
crossref
Published In
Breast Cancer Research
Volume
16
Issue
6
Publish Date
2014
DOI
10.1186/s13058-014-0471-1

Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production.

Activation of the inflammatory response is accompanied by a metabolic shift to aerobic glycolysis. Here we identify histone deacetylase 4 (HDAC4) as a new component of the immunometabolic program. We show that HDAC4 is required for efficient inflammatory cytokine production activated by lipopolysaccharide (LPS). Surprisingly, prolonged LPS treatment leads to HDAC4 degradation. LPS-induced HDAC4 degradation requires active glycolysis controlled by GSK3β and inducible nitric oxide synthase (iNOS). Inhibition of GSK3β or iNOS suppresses nitric oxide (NO) production, glycolysis, and HDAC4 degradation. We present evidence that sustained glycolysis induced by LPS treatment activates caspase-3, which cleaves HDAC4 and triggers its degradation. Of importance, a caspase-3-resistant mutant HDAC4 escapes LPS-induced degradation and prolongs inflammatory cytokine production. Our findings identify the GSK3β-iNOS-NO axis as a critical signaling cascade that couples inflammation to metabolic reprogramming and a glycolysis-driven negative feedback mechanism that limits inflammatory response by triggering HDAC4 degradation.

Authors
Wang, B; Liu, T-Y; Lai, C-H; Rao, Y-H; Choi, M-C; Chi, J-T; Dai, J-W; Rathmell, JC; Yao, T-P
MLA Citation
Wang, B, Liu, T-Y, Lai, C-H, Rao, Y-H, Choi, M-C, Chi, J-T, Dai, J-W, Rathmell, JC, and Yao, T-P. "Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production." Molecular biology of the cell 25.21 (November 2014): 3300-3307.
PMID
25187650
Source
epmc
Published In
Molecular Biology of the Cell
Volume
25
Issue
21
Publish Date
2014
Start Page
3300
End Page
3307
DOI
10.1091/mbc.e13-12-0757

A joint analysis of metabolomics and genetics of breast cancer.

Remodeling of cellular metabolism appears to be a consequence and possibly a cause of oncogenic transformation in human cancers. Specific aspects of altered tumor metabolism may be amenable to therapeutic intervention and could be coordinated with other targeted therapies. In breast cancer, the genetic landscape has been defined most comprehensively in efforts such as The Cancer Genome Atlas (TCGA). However, little is known about how alterations of tumor metabolism correlate with this landscape.In total 25 cancers (23 fully analyzed by TCGA) and 5 normal breast specimens were analyzed by gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry, quantitating 399 identifiable metabolites.We found strong differences correlated with hormone receptor status with 18% of the metabolites elevated in estrogen receptor negative (ER-) cancers compared to estrogen receptor positive (ER+) including many glycolytic and glycogenolytic intermediates consistent with increased Warburg effects. Glutathione (GSH) pathway components were also elevated in ER- tumors consistent with an increased requirement for handling higher levels of oxidative stress. Additionally, ER- tumors had high levels of the oncometabolite 2-hydroxyglutarate (2-HG) and the immunomodulatory tryptophan metabolite kynurenine. Kynurenine levels were correlated with the expression of tryptophan-degrading enzyme (IDO1). However, high levels of 2-HG were not associated with somatic mutations or expression levels of IDH1 or IDH2. BRCA1 mRNA levels were positively associated with coenzyme A, acetyl coenzyme A, and GSH and negatively associated with multiple lipid species, supporting the regulation of ACC1 and NRF2 by BRCA1. Different driver mutations were associated with distinct patterns of specific metabolites, such as lower levels of several lipid-glycerophosphocholines in tumors with mutated TP53. A strong metabolomic signature associated with proliferation rate was also observed; the metabolites in this signature overlap broadly with metabolites that define ER status as receptor status and proliferation rate were correlated.The addition of metabolomic profiles to the public domain TCGA dataset provides an important new tool for discovery and hypothesis testing of the genetic regulation of tumor metabolism. Particular sets of metabolites may reveal insights into the metabolic dysregulation that underlie the heterogeneity of breast cancer.

Authors
Tang, X; Lin, C-C; Spasojevic, I; Iversen, ES; Chi, J-T; Marks, JR
MLA Citation
Tang, X, Lin, C-C, Spasojevic, I, Iversen, ES, Chi, J-T, and Marks, JR. "A joint analysis of metabolomics and genetics of breast cancer." Breast cancer research : BCR 16.4 (August 5, 2014): 415-.
PMID
25091696
Source
epmc
Published In
Breast Cancer Research
Volume
16
Issue
4
Publish Date
2014
Start Page
415
DOI
10.1186/s13058-014-0415-9

Alveolar rhabdomyosarcoma-associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression.

Alveolar rhabdomyosarcoma (aRMS) is an aggressive sarcoma of skeletal muscle characterized by expression of the paired box 3-forkhead box protein O1 (PAX3-FOXO1) fusion oncogene. Despite its discovery nearly two decades ago, the mechanisms by which PAX3-FOXO1 drives tumor development are not well characterized. Previously, we reported that PAX3-FOXO1 supports aRMS initiation by enabling bypass of cellular senescence checkpoints. We have now found that this bypass occurs in part through PAX3-FOXO1-mediated upregulation of RASSF4, a Ras-association domain family (RASSF) member. RASSF4 expression was upregulated in PAX3-FOXO1-positive aRMS cell lines and tumors. Enhanced RASSF4 expression promoted cell cycle progression, senescence evasion, and tumorigenesis through inhibition of the Hippo pathway tumor suppressor MST1. We also found that the downstream Hippo pathway target Yes-associated protein 1 (YAP), which is ordinarily restrained by Hippo signaling, was upregulated in RMS tumors. These data suggest that Hippo pathway dysfunction promotes RMS. This work provides evidence for Hippo pathway suppression in aRMS and demonstrates a progrowth role for RASSF4. Additionally, we identify a mechanism used by PAX3-FOXO1 to inhibit MST1 signaling and promote tumorigenesis in aRMS.

Authors
Crose, LES; Galindo, KA; Kephart, JG; Chen, C; Fitamant, J; Bardeesy, N; Bentley, RC; Galindo, RL; Chi, J-TA; Linardic, CM
MLA Citation
Crose, LES, Galindo, KA, Kephart, JG, Chen, C, Fitamant, J, Bardeesy, N, Bentley, RC, Galindo, RL, Chi, J-TA, and Linardic, CM. "Alveolar rhabdomyosarcoma-associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression." The Journal of clinical investigation 124.1 (January 2014): 285-296.
PMID
24334454
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
1
Publish Date
2014
Start Page
285
End Page
296
DOI
10.1172/jci67087

Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress.

A variety of oncogenic and environmental factors alter tumor metabolism to serve the distinct cellular biosynthetic and bioenergetic needs present during oncogenesis. Extracellular acidosis is a common microenvironmental stress in solid tumors, but little is known about its metabolic influence, particularly when present in the absence of hypoxia. In order to characterize the extent of tumor cell metabolic adaptations to acidosis, we employed stable isotope tracers to examine how acidosis impacts glucose, glutamine, and palmitate metabolism in breast cancer cells exposed to extracellular acidosis.Acidosis increased both glutaminolysis and fatty acid β-oxidation, which contribute metabolic intermediates to drive the tricarboxylic acid cycle (TCA cycle) and ATP generation. Acidosis also led to a decoupling of glutaminolysis and novel glutathione (GSH) synthesis by repressing GCLC/GCLM expression. We further found that acidosis redirects glucose away from lactate production and towards the oxidative branch of the pentose phosphate pathway (PPP). These changes all serve to increase nicotinamide adenine dinucleotide phosphate (NADPH) production and counter the increase in reactive oxygen species (ROS) present under acidosis. The reduced novel GSH synthesis under acidosis may explain the increased demand for NADPH to recycle existing pools of GSH. Interestingly, acidosis also disconnected novel ribose synthesis from the oxidative PPP, seemingly to reroute PPP metabolites to the TCA cycle. Finally, we found that acidosis activates p53, which contributes to both the enhanced PPP and increased glutaminolysis, at least in part, through the induction of G6PD and GLS2 genes.Acidosis alters the cellular metabolism of several major metabolites, which induces a significant degree of metabolic inflexibility. Cells exposed to acidosis largely rely upon mitochondrial metabolism for energy generation to the extent that metabolic intermediates are redirected away from several other critical metabolic processes, including ribose and glutathione synthesis. These alterations lead to both a decrease in cellular proliferation and increased sensitivity to ROS. Collectively, these data reveal a role for p53 in cellular metabolic reprogramming under acidosis, in order to permit increased bioenergetic capacity and ROS neutralization. Understanding the metabolic adaptations that cancer cells make under acidosis may present opportunities to generate anti-tumor therapeutic agents that are more tumor-specific.

Authors
Lamonte, G; Tang, X; Chen, JL-Y; Wu, J; Ding, C-KC; Keenan, MM; Sangokoya, C; Kung, H-N; Ilkayeva, O; Boros, LG; Newgard, CB; Chi, J-T
MLA Citation
Lamonte, G, Tang, X, Chen, JL-Y, Wu, J, Ding, C-KC, Keenan, MM, Sangokoya, C, Kung, H-N, Ilkayeva, O, Boros, LG, Newgard, CB, and Chi, J-T. "Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress." Cancer & metabolism 1.1 (December 23, 2013): 23-.
PMID
24359630
Source
epmc
Published In
Cancer and Metabolism
Volume
1
Issue
1
Publish Date
2013
Start Page
23
DOI
10.1186/2049-3002-1-23

Erratum: Fish oil slows prostate cancer xenograft growth relative to other dietary fats and is associated with decreased mitochondrial and insulin pathway gene expression (Prostate Cancer and Prostatic Diseases (2013) 16 (398) DOI:10.1038/pcan.2013.29)

Authors
Lloyd, JC; Masko, EM; Wu, C; Keenan, MM; Pilla, DM; Aronson, WJ; Chi, JT; Freedland, SJ
MLA Citation
Lloyd, JC, Masko, EM, Wu, C, Keenan, MM, Pilla, DM, Aronson, WJ, Chi, JT, and Freedland, SJ. "Erratum: Fish oil slows prostate cancer xenograft growth relative to other dietary fats and is associated with decreased mitochondrial and insulin pathway gene expression (Prostate Cancer and Prostatic Diseases (2013) 16 (398) DOI:10.1038/pcan.2013.29)." Prostate Cancer and Prostatic Diseases 16.4 (December 1, 2013): 398-.
Source
scopus
Published In
Prostate Cancer and Prostatic Diseases
Volume
16
Issue
4
Publish Date
2013
Start Page
398
DOI
10.1038/pcan.2013.29

Fish oil slows prostate cancer xenograft growth relative to other dietary fats and is associated with decreased mitochondrial and insulin pathway gene expression

BACKGROUND:Previous mouse studies suggest that decreasing dietary fat content can slow prostate cancer (PCa) growth. To our knowledge, no study has yet compared the effect of multiple different fats on PCa progression. We sought to systematically compare the effect of fish oil, olive oil, corn oil and animal fat on PCa progression.METHODS:A total of 96 male severe combined immunodeficient mice were injected with LAPC-4 human PCa cells. Two weeks following injection, mice were randomized to a Western diet based on fish oil, olive oil, corn oil or animal fat (35% kilocalories from fat). Animals were euthanized when tumor volumes reached 1000 mm 3. Serum was collected at death and assayed for PSA, insulin, insulin-like growth factor-1 (IGF-1), IGF-1-binding protein-3 and prostaglandin E-2 (PGE-2) levels. Tumors were also assayed for PGE-2 and cyclooxygenase-2 levels, and global gene expression was analyzed using Affymetrix microarrays.RESULTS:Mice weights and tumor volumes were equivalent across groups at randomization. Overall, fish oil consumption was associated with improved survival relative to other dietary groups (P=0.014). On gene expression analyses, the fish oil group had decreased signal in pathways related to mitochondrial physiology and insulin synthesis/secretion. CONCLUSIONS:In this xenograft model, we found that consuming a diet in which fish oil was the only fat source slowed tumor growth and improved survival compared with that in mice consuming diets composed of olive oil, corn oil or animal fat. Although prior studies showed that the amount of fat is important for PCa growth, this study suggests that the type of dietary fat consumed may also be important. © 2013 Macmillan Publishers Limited All rights reserved.

Authors
Lloyd, JC; Masko, EM; Wu, C; Keenan, MM; Pilla, DM; Aronson, WJ; Chi, JT; Freedland, SJ
MLA Citation
Lloyd, JC, Masko, EM, Wu, C, Keenan, MM, Pilla, DM, Aronson, WJ, Chi, JT, and Freedland, SJ. "Fish oil slows prostate cancer xenograft growth relative to other dietary fats and is associated with decreased mitochondrial and insulin pathway gene expression." Prostate Cancer and Prostatic Diseases 16.4 (December 1, 2013): 285-291.
Source
scopus
Published In
Prostate Cancer and Prostatic Diseases
Volume
16
Issue
4
Publish Date
2013
Start Page
285
End Page
291
DOI
10.1038/pcan.2013.19

Fish oil slows prostate cancer xenograft growth relative to other dietary fats and is associated with decreased mitochondrial and insulin pathway gene expression.

BACKGROUND: Previous mouse studies suggest that decreasing dietary fat content can slow prostate cancer (PCa) growth. To our knowledge, no study has yet compared the effect of multiple different fats on PCa progression. We sought to systematically compare the effect of fish oil, olive oil, corn oil and animal fat on PCa progression. METHODS: A total of 96 male severe combined immunodeficient mice were injected with LAPC-4 human PCa cells. Two weeks following injection, mice were randomized to a Western diet based on fish oil, olive oil, corn oil or animal fat (35% kilocalories from fat). Animals were euthanized when tumor volumes reached 1000 mm(3). Serum was collected at death and assayed for PSA, insulin, insulin-like growth factor-1 (IGF-1), IGF-1-binding protein-3 and prostaglandin E-2 (PGE-2) levels. Tumors were also assayed for PGE-2 and cyclooxygenase-2 levels, and global gene expression was analyzed using Affymetrix microarrays. RESULTS: Mice weights and tumor volumes were equivalent across groups at randomization. Overall, fish oil consumption was associated with improved survival relative to other dietary groups (P=0.014). On gene expression analyses, the fish oil group had decreased signal in pathways related to mitochondrial physiology and insulin synthesis/secretion. CONCLUSIONS: In this xenograft model, we found that consuming a diet in which fish oil was the only fat source slowed tumor growth and improved survival compared with that in mice consuming diets composed of olive oil, corn oil or animal fat. Although prior studies showed that the amount of fat is important for PCa growth, this study suggests that the type of dietary fat consumed may also be important.

Authors
Lloyd, JC; Masko, EM; Wu, C; Keenan, MM; Pilla, DM; Aronson, WJ; Chi, J-T; Freedland, SJ
MLA Citation
Lloyd, JC, Masko, EM, Wu, C, Keenan, MM, Pilla, DM, Aronson, WJ, Chi, J-T, and Freedland, SJ. "Fish oil slows prostate cancer xenograft growth relative to other dietary fats and is associated with decreased mitochondrial and insulin pathway gene expression." Prostate Cancer Prostatic Dis 16.4 (December 2013): 285-291.
PMID
23877027
Source
pubmed
Published In
Prostate Cancer and Prostatic Diseases
Volume
16
Issue
4
Publish Date
2013
Start Page
285
End Page
291
DOI
10.1038/pcan.2013.19

Fish oil slows prostate cancer xenograft growth relative to other dietary fats and is associated with decreased mitochondrial and insulin pathway gene expression.

Authors
Lloyd, JC; Masko, EM; Wu, C; Keenan, MM; Pilla, DM; Aronson, WJ; Chi, JT; Freedland, SJ
MLA Citation
Lloyd, JC, Masko, EM, Wu, C, Keenan, MM, Pilla, DM, Aronson, WJ, Chi, JT, and Freedland, SJ. "Fish oil slows prostate cancer xenograft growth relative to other dietary fats and is associated with decreased mitochondrial and insulin pathway gene expression." Prostate Cancer Prostatic Dis 16.4 (December 2013): 398-.
PMID
24217775
Source
pubmed
Published In
Prostate Cancer and Prostatic Diseases
Volume
16
Issue
4
Publish Date
2013
Start Page
398
DOI
10.1038/pcan.2013.29

Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events.

The aim of this study was to develop ribonucleic acid (RNA) profiles that could serve as novel biomarkers for the response to aspirin.Aspirin reduces death and myocardial infarction (MI), suggesting that aspirin interacts with biological pathways that may underlie these events.Aspirin was administered, followed by whole-blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1) (n = 50) and 2 validation cohorts of healthy volunteers (HV2) (n = 53) and outpatient cardiology patients (OPC) (n = 25). Platelet function was assessed using the platelet function score (PFS) in HV1 and HV2 and the VerifyNow Aspirin Test (Accumetrics, Inc., San Diego, California) in OPC. Bayesian sparse factor analysis identified sets of coexpressed transcripts, which were examined for associations with PFS in HV1 and validated in HV2 and OPC. Proteomic analysis confirmed the association of validated transcripts in platelet proteins. Validated gene sets were tested for association with death or MI in 2 patient cohorts (n = 587 total) from RNA samples collected at cardiac catheterization.A set of 60 coexpressed genes named the "aspirin response signature" (ARS) was associated with PFS in HV1 (r = -0.31, p = 0.03), HV2 (r = -0.34, Bonferroni p = 0.03), and OPC (p = 0.046). Corresponding proteins for the 17 ARS genes were identified in the platelet proteome, of which 6 were associated with PFS. The ARS was associated with death or MI in both patient cohorts (odds ratio: 1.2 [p = 0.01]; hazard ratio: 1.5 [p = 0.001]), independent of cardiovascular risk factors. Compared with traditional risk factors, reclassification (net reclassification index = 31% to 37%, p ≤ 0.0002) was improved by including the ARS or 1 of its genes, ITGA2B.RNA profiles of platelet-specific genes are novel biomarkers for identifying patients who do not respond adequately to aspirin and who are at risk for death or MI.

Authors
Voora, D; Cyr, D; Lucas, J; Chi, J-T; Dungan, J; McCaffrey, TA; Katz, R; Newby, LK; Kraus, WE; Becker, RC; Ortel, TL; Ginsburg, GS
MLA Citation
Voora, D, Cyr, D, Lucas, J, Chi, J-T, Dungan, J, McCaffrey, TA, Katz, R, Newby, LK, Kraus, WE, Becker, RC, Ortel, TL, and Ginsburg, GS. "Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events." Journal of the American College of Cardiology 62.14 (October 2013): 1267-1276.
PMID
23831034
Source
epmc
Published In
JACC - Journal of the American College of Cardiology
Volume
62
Issue
14
Publish Date
2013
Start Page
1267
End Page
1276
DOI
10.1016/j.jacc.2013.05.073

Understanding the tumor microenvironment and radioresistance by combining functional imaging with global gene expression.

The objective of this review is to present an argument for performing joint analyses between functional imaging with global gene expression studies. The reason for making this link is that tumor microenvironmental influences on functional imaging can be uncovered. Such knowledge can lead to (1) more informed decisions regarding how to use functional imaging to guide therapy and (2) discovery of new therapeutic targets. As such, this approach could lead to identification of patients who need aggressive treatment tailored toward the phenotype of their tumor vs those who could be spared treatment that carries risk for more normal tissue complications. Only a handful of papers have been published on this topic thus far, but all show substantial promise.

Authors
Dewhirst, MW; Chi, J-T
MLA Citation
Dewhirst, MW, and Chi, J-T. "Understanding the tumor microenvironment and radioresistance by combining functional imaging with global gene expression." Semin Radiat Oncol 23.4 (October 2013): 296-305. (Review)
PMID
24012344
Source
pubmed
Published In
Seminars in Radiation Oncology
Volume
23
Issue
4
Publish Date
2013
Start Page
296
End Page
305
DOI
10.1016/j.semradonc.2013.05.004

Acidosis Activation of the Proton-Sensing GPR4 Receptor Stimulates Vascular Endothelial Cell Inflammatory Responses Revealed by Transcriptome Analysis

Acidic tissue microenvironment commonly exists in inflammatory diseases, tumors, ischemic organs, sickle cell disease, and many other pathological conditions due to hypoxia, glycolytic cell metabolism and deficient blood perfusion. However, the molecular mechanisms by which cells sense and respond to the acidic microenvironment are not well understood. GPR4 is a proton-sensing receptor expressed in endothelial cells and other cell types. The receptor is fully activated by acidic extracellular pH but exhibits lesser activity at the physiological pH 7.4 and minimal activity at more alkaline pH. To delineate the function and signaling pathways of GPR4 activation by acidosis in endothelial cells, we compared the global gene expression of the acidosis response in primary human umbilical vein endothelial cells (HUVEC) with varying level of GPR4. The results demonstrated that acidosis activation of GPR4 in HUVEC substantially increased the expression of a number of inflammatory genes such as chemokines, cytokines, adhesion molecules, NF-κB pathway genes, and prostaglandin-endoperoxidase synthase 2 (PTGS2 or COX-2) and stress response genes such as ATF3 and DDIT3 (CHOP). Similar GPR4-mediated acidosis induction of the inflammatory genes was also noted in other types of endothelial cells including human lung microvascular endothelial cells and pulmonary artery endothelial cells. Further analyses indicated that the NF-κB pathway was important for the acidosis/GPR4-induced inflammatory gene expression. Moreover, acidosis activation of GPR4 increased the adhesion of HUVEC to U937 monocytic cells under a flow condition. Importantly, treatment with a recently identified GPR4 antagonist significantly reduced the acidosis/GPR4-mediated endothelial cell inflammatory response. Taken together, these results show that activation of GPR4 by acidosis stimulates the expression of a wide range of inflammatory genes in endothelial cells. Such inflammatory response can be suppressed by GPR4 small molecule inhibitors and hold potential therapeutic value. © 2013 Dong et al.

Authors
Dong, L; Li, Z; Leffler, NR; Asch, AS; Chi, J-T; Yang, LV
MLA Citation
Dong, L, Li, Z, Leffler, NR, Asch, AS, Chi, J-T, and Yang, LV. "Acidosis Activation of the Proton-Sensing GPR4 Receptor Stimulates Vascular Endothelial Cell Inflammatory Responses Revealed by Transcriptome Analysis." PLoS ONE 8.4 (2013).
PMID
23613998
Source
scival
Published In
PloS one
Volume
8
Issue
4
Publish Date
2013
DOI
10.1371/journal.pone.0061991

Iron-Responsive miR-485-3p Regulates Cellular Iron Homeostasis by Targeting Ferroportin

Ferroportin (FPN) is the only known cellular iron exporter in mammalian cells and plays a critical role in the maintenance of both cellular and systemic iron balance. During iron deprivation, the translation of FPN is repressed by iron regulatory proteins (IRPs), which bind to the 5′ untranslated region (UTR), to reduce iron export and preserve cellular iron. Here, we report a novel iron-responsive mechanism for the post-transcriptional regulation of FPN, mediated by miR-485-3p, which is induced during iron deficiency and represses FPN expression by directly targeting the FPN 3′UTR. The overexpression of miR-485-3p represses FPN expression and leads to increased cellular ferritin levels, consistent with increased cellular iron. Conversely, both inhibition of miR-485-3p activity and mutation of the miR-485-3p target sites on the FPN 3′UTR are able to relieve FPN repression and lead to decreased cellular iron levels. Together, these findings support a model that includes both IRPs and microRNAs as iron-responsive post-transcriptional regulators of FPN. The involvement of microRNA in the iron-responsive regulation of FPN offers additional stability and fine-tuning of iron homeostasis within different cellular contexts. MiR-485-3p-mediated repression of FPN may also offer a novel potential therapeutic mechanism for circumventing hepcidin-resistant mechanisms responsible for some iron overload diseases. © 2013 Sangokoya et al.

Authors
Sangokoya, C; Doss, JF; Chi, J-T
MLA Citation
Sangokoya, C, Doss, JF, and Chi, J-T. "Iron-Responsive miR-485-3p Regulates Cellular Iron Homeostasis by Targeting Ferroportin." PLoS Genetics 9.4 (2013).
PMID
23593016
Source
scival
Published In
PLoS genetics
Volume
9
Issue
4
Publish Date
2013
DOI
10.1371/journal.pgen.1003408

Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer.

Lactate accumulation in tumors has been associated with metastases and poor overall survival in cancer patients. Lactate promotes angiogenesis and metastasis, providing rationale for understanding how it is processed by cells. The concentration of lactate in tumors is a balance between the amount produced, amount carried away by vasculature and if/how it is catabolized by aerobic tumor or stromal cells. We examined lactate metabolism in human normal and breast tumor cell lines and rat breast cancer: 1. at relevant concentrations, 2. under aerobic vs. hypoxic conditions, 3. under conditions of normo vs. hypoglucosis. We also compared the avidity of tumors for lactate vs. glucose and identified key lactate catabolites to reveal how breast cancer cells process it. Lactate was non-toxic at clinically relevant concentrations. It was taken up and catabolized to alanine and glutamate by all cell lines. Kinetic uptake rates of lactate in vivo surpassed that of glucose in R3230Ac mammary carcinomas. The uptake appeared specific to aerobic tumor regions, consistent with the proposed "metabolic symbiont" model; here lactate produced by hypoxic cells is used by aerobic cells. We investigated whether treatment with alpha-cyano-4-hydroxycinnamate (CHC), a MCT1 inhibitor, would kill cells in the presence of high lactate. Both 0.1 mM and 5 mM CHC prevented lactate uptake in R3230Ac cells at lactate concentrations at ≤ 20 mM but not at 40 mM. 0.1 mM CHC was well-tolerated by R3230Ac and MCF7 cells, but 5 mM CHC killed both cell lines ± lactate, indicating off-target effects. This study showed that breast cancer cells tolerate and use lactate at clinically relevant concentrations in vitro (± glucose) and in vivo. We provided additional support for the metabolic symbiont model and discovered that breast cells prevailingly take up and catabolize lactate, providing rationale for future studies on manipulation of lactate catabolism pathways for therapy.

Authors
Kennedy, KM; Scarbrough, PM; Ribeiro, A; Richardson, R; Yuan, H; Sonveaux, P; Landon, CD; Chi, J-T; Pizzo, S; Schroeder, T; Dewhirst, MW
MLA Citation
Kennedy, KM, Scarbrough, PM, Ribeiro, A, Richardson, R, Yuan, H, Sonveaux, P, Landon, CD, Chi, J-T, Pizzo, S, Schroeder, T, and Dewhirst, MW. "Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer. (Published online)" PLoS One 8.9 (2013): e75154-.
PMID
24069390
Source
pubmed
Published In
PloS one
Volume
8
Issue
9
Publish Date
2013
Start Page
e75154
DOI
10.1371/journal.pone.0075154

A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation.

Monoallelic point mutations of the NADP(+)-dependent isocitrate dehydrogenases IDH1 and IDH2 occur frequently in gliomas, acute myeloid leukemias, and chondromas, and display robust association with specific DNA hypermethylation signatures. Here we show that heterozygous expression of the IDH1(R132H) allele is sufficient to induce the genome-wide alterations in DNA methylation characteristic of these tumors. Using a gene-targeting approach, we knocked-in a single copy of the most frequently observed IDH1 mutation, R132H, into a human cancer cell line and profiled changes in DNA methylation at over 27,000 CpG dinucleotides relative to wild-type parental cells. We find that IDH1(R132H/WT) mutation induces widespread alterations in DNA methylation, including hypermethylation of 2010 and hypomethylation of 842 CpG loci. We demonstrate that many of these alterations are consistent with those observed in IDH1-mutant and G-CIMP+ primary gliomas and can segregate IDH wild-type and mutated tumors as well as those exhibiting the G-CIMP phenotype in unsupervised analysis of two primary glioma cohorts. Further, we show that the direction of IDH1(R132H/WT)-mediated DNA methylation change is largely dependent upon preexisting DNA methylation levels, resulting in depletion of moderately methylated loci. Additionally, whereas the levels of multiple histone H3 and H4 methylation modifications were globally increased, consistent with broad inhibition of histone demethylation, hypermethylation at H3K9 in particular accompanied locus-specific DNA hypermethylation at several genes down-regulated in IDH1(R132H/WT) knock-in cells. These data provide insight on epigenetic alterations induced by IDH1 mutations and support a causal role for IDH1(R132H/WT) mutants in driving epigenetic instability in human cancer cells.

Authors
Duncan, CG; Barwick, BG; Jin, G; Rago, C; Kapoor-Vazirani, P; Powell, DR; Chi, J-T; Bigner, DD; Vertino, PM; Yan, H
MLA Citation
Duncan, CG, Barwick, BG, Jin, G, Rago, C, Kapoor-Vazirani, P, Powell, DR, Chi, J-T, Bigner, DD, Vertino, PM, and Yan, H. "A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation." Genome Res 22.12 (December 2012): 2339-2355.
PMID
22899282
Source
pubmed
Published In
Genome research
Volume
22
Issue
12
Publish Date
2012
Start Page
2339
End Page
2355
DOI
10.1101/gr.132738.111

Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways.

Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesis. Here we profile the global loci targeted by MLL2. A combinatorial analysis of the MLL2 binding profile and gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines identified direct transcriptional target genes and revealed the connection of MLL2 to multiple cellular signaling pathways, including the p53 pathway, cAMP-mediated signaling, and cholestasis signaling. In particular, we demonstrate that MLL2 participates in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription. Our results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations.

Authors
Guo, C; Chang, C-C; Wortham, M; Chen, LH; Kernagis, DN; Qin, X; Cho, Y-W; Chi, J-T; Grant, GA; McLendon, RE; Yan, H; Ge, K; Papadopoulos, N; Bigner, DD; He, Y
MLA Citation
Guo, C, Chang, C-C, Wortham, M, Chen, LH, Kernagis, DN, Qin, X, Cho, Y-W, Chi, J-T, Grant, GA, McLendon, RE, Yan, H, Ge, K, Papadopoulos, N, Bigner, DD, and He, Y. "Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways." Proc Natl Acad Sci U S A 109.43 (October 23, 2012): 17603-17608.
PMID
23045699
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
109
Issue
43
Publish Date
2012
Start Page
17603
End Page
17608
DOI
10.1073/pnas.1208807109

Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance.

Erythrocytes carrying a variant hemoglobin allele (HbS), which causes sickle cell disease and resists infection by the malaria parasite Plasmodium falciparum. The molecular basis of this resistance, which has long been recognized as multifactorial, remains incompletely understood. Here we show that the dysregulated microRNA (miRNA) composition, of either heterozygous HbAS or homozygous HbSS erythrocytes, contributes to resistance against P. falciparum. During the intraerythrocytic life cycle of P. falciparum, a subset of erythrocyte miRNAs translocate into the parasite. Two miRNAs, miR-451 and let-7i, were highly enriched in HbAS and HbSS erythrocytes, and these miRNAs, along with miR-223, negatively regulated parasite growth. Surprisingly, we found that miR-451 and let-7i integrated into essential parasite messenger RNAs and, via impaired ribosomal loading, resulted in translational inhibition. Hence, sickle cell erythrocytes exhibit cell-intrinsic resistance to malaria in part through an atypical miRNA activity, which may represent a unique host defense strategy against complex eukaryotic pathogens.

Authors
LaMonte, G; Philip, N; Reardon, J; Lacsina, JR; Majoros, W; Chapman, L; Thornburg, CD; Telen, MJ; Ohler, U; Nicchitta, CV; Haystead, T; Chi, J-T
MLA Citation
LaMonte, G, Philip, N, Reardon, J, Lacsina, JR, Majoros, W, Chapman, L, Thornburg, CD, Telen, MJ, Ohler, U, Nicchitta, CV, Haystead, T, and Chi, J-T. "Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance." Cell Host Microbe 12.2 (August 16, 2012): 187-199.
PMID
22901539
Source
pubmed
Published In
Cell Host and Microbe
Volume
12
Issue
2
Publish Date
2012
Start Page
187
End Page
199
DOI
10.1016/j.chom.2012.06.007

Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy.

To develop an integrated metric of non-COX-1-dependent platelet function (NCDPF) to measure the temporal response to aspirin in healthy volunteers and diabetics. NCDPF on aspirin demonstrates wide variability, despite suppression of COX-1. Although a variety of NCDPF assays are available, no standard exists and their reproducibility is not established. We administered 325 mg/day aspirin to two cohorts of volunteers (HV1, n = 52, and HV2, n = 96) and diabetics (DM, n = 74) and measured NCDPF using epinephrine, collagen, and ADP aggregometry and PFA100 (collagen/epi) before (Pre), after one dose (Post), and after several weeks (Final). COX-1 activity was assessed with arachidonic acid aggregometry (AAA). The primary outcome of the study, the platelet function score (PFS), was derived from a principal components analysis of NCDPF measures. The PFS strongly correlated with each measure of NCDPF in each cohort. After 2 or 4 weeks of daily aspirin the Final PFS strongly correlated (r > 0.7, P < 0.0001) and was higher (P < 0.01) than the Post PFS. The magnitude and direction of the change in PFS (Final–Post) in an individual subject was moderately inversely proportional to the Post PFS in HV1 (r = -0.45), HV2 (r = -0.54), DM (r = -0.68), P < 0.0001 for all. AAA remained suppressed during aspirin therapy. The PFS summarizes multiple measures of NCDPF. Despite suppression of COX-1 activity, NCDPF during aspirin therapy is predictably dynamic: those with heightened NCDPF continue to decline whereas those with low/normal NCDPF return to pre-aspirin levels over time.

Authors
Voora, D; Ortel, TL; Lucas, JE; Chi, J-T; Becker, RC; Ginsburg, GS
MLA Citation
Voora, D, Ortel, TL, Lucas, JE, Chi, J-T, Becker, RC, and Ginsburg, GS. "Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy." J Thromb Thrombolysis 33.3 (April 2012): 246-257.
PMID
22294277
Source
pubmed
Published In
Journal of Thrombosis and Thrombolysis
Volume
33
Issue
3
Publish Date
2012
Start Page
246
End Page
257
DOI
10.1007/s11239-012-0683-0

Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs.

Within solid tumor microenvironments, lactic acidosis, and hypoxia each have powerful effects on cancer pathophysiology. However, the influence that these processes exert on each other is unknown. Here, we report that a significant portion of the transcriptional response to hypoxia elicited in cancer cells is abolished by simultaneous exposure to lactic acidosis. In particular, lactic acidosis abolished stabilization of HIF-1α protein which occurs normally under hypoxic conditions. In contrast, lactic acidosis strongly synergized with hypoxia to activate the unfolded protein response (UPR) and an inflammatory response, displaying a strong similarity to ATF4-driven amino acid deprivation responses (AAR). In certain breast tumors and breast tumor cells examined, an integrative analysis of gene expression and array CGH data revealed DNA copy number alterations at the ATF4 locus, an important activator of the UPR/AAR pathway. In this setting, varying ATF4 levels influenced the survival of cells after exposure to hypoxia and lactic acidosis. Our findings reveal that the condition of lactic acidosis present in solid tumors inhibits canonical hypoxia responses and activates UPR and inflammation responses. Furthermore, these data suggest that ATF4 status may be a critical determinant of the ability of cancer cells to adapt to oxygen and acidity fluctuations in the tumor microenvironment, perhaps linking short-term transcriptional responses to long-term selection for copy number alterations in cancer cells.

Authors
Tang, X; Lucas, JE; Chen, JL-Y; LaMonte, G; Wu, J; Wang, MC; Koumenis, C; Chi, J-T
MLA Citation
Tang, X, Lucas, JE, Chen, JL-Y, LaMonte, G, Wu, J, Wang, MC, Koumenis, C, and Chi, J-T. "Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs." Cancer Res 72.2 (January 15, 2012): 491-502.
PMID
22135092
Source
pubmed
Published In
Cancer Research
Volume
72
Issue
2
Publish Date
2012
Start Page
491
End Page
502
DOI
10.1158/0008-5472.CAN-11-2076

Associations between Intake of Folate, Methionine, and Vitamins B-12, B-6 and Prostate Cancer Risk in American Veterans.

Prostate cancer (PC) is the second leading cause of cancer death in men. Recent reports suggest that excess of nutrients involved in the one-carbon metabolism pathway increases PC risk; however, empirical data are lacking. Veteran American men (272 controls and 144 PC cases) who attended the Durham Veteran American Medical Center between 2004-2009 were enrolled into a case-control study. Intake of folate, vitamin B12, B6, and methionine were measured using a food frequency questionnaire. Regression models were used to evaluate the association among one-carbon cycle nutrients, MTHFR genetic variants, and prostate cancer. Higher dietary methionine intake was associated with PC risk (OR = 2.1; 95%CI 1.1-3.9) The risk was most pronounced in men with Gleason sum <7 (OR = 2.75; 95%CI 1.32- 5.73). The association of higher methionine intake and PC risk was only apparent in men who carried at least one MTHFR A1298C allele (OR = 6.7; 95%CI = 1.6-27.8), compared to MTHFR A1298A noncarrier men (OR = 0.9; 95%CI = 0.24-3.92) (p-interaction = 0.045). There was no evidence for associations between B vitamins (folate, B12, and B6) and PC risk. Our results suggest that carrying the MTHFR A1298C variants modifies the association between high methionine intake and PC risk. Larger studies are required to validate these findings.

Authors
Vidal, AC; Grant, DJ; Williams, CD; Masko, E; Allott, EH; Shuler, K; McPhail, M; Gaines, A; Calloway, E; Gerber, L; Chi, J-T; Freedland, SJ; Hoyo, C
MLA Citation
Vidal, AC, Grant, DJ, Williams, CD, Masko, E, Allott, EH, Shuler, K, McPhail, M, Gaines, A, Calloway, E, Gerber, L, Chi, J-T, Freedland, SJ, and Hoyo, C. "Associations between Intake of Folate, Methionine, and Vitamins B-12, B-6 and Prostate Cancer Risk in American Veterans." J Cancer Epidemiol 2012 (2012): 957467-.
Website
http://hdl.handle.net/10161/6105
PMID
22927849
Source
pubmed
Published In
Journal of Cancer Epidemiology
Volume
2012
Publish Date
2012
Start Page
957467
DOI
10.1155/2012/957467

Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy

To develop an integrated metric of non-COX-1- dependent platelet function (NCDPF) to measure the temporal response to aspirin in healthy volunteers and diabetics. NCDPF on aspirin demonstrates wide variability, despite suppression of COX-1. Although a variety of NCDPF assays are available, no standard exists and their reproducibility is not established. We administered 325 mg/day aspirin to two cohorts of volunteers (HV1, n = 52, and HV2, n = 96) and diabetics (DM, n = 74) and measured NCDPF using epinephrine, collagen, and ADP aggregometry and PFA100 (collagen/epi) before (Pre), after one dose (Post), and after several weeks (Final). COX-1 activity was assessed with arachidonic acid aggregometry (AAA). The primary outcome of the study, the platelet function score (PFS), was derived from a principal components analysis of NCDPF measures. The PFS strongly correlated with each measure of NCDPF in each cohort. After 2 or 4 weeks of daily aspirin the Final PFS strongly correlated (r>0.7, P<0.0001) and was higher (P<0.01) than the Post PFS. The magnitude and direction of the change in PFS (Final-Post) in an individual subject was moderately inversely proportional to the Post PFS in HV1 (r = -0.45), HV2 (r = -0.54), DM (r = -0.68), P<0.0001 for all. AAA remained suppressed during aspirin therapy. The PFS summarizes multiple measures of NCDPF. Despite suppression of COX-1 activity, NCDPF during aspirin therapy is predictably dynamic: those with heightened NCDPF continue to decline whereas those with low/normal NCDPF return to pre-aspirin levels over time. © Springer Science+Business Media, LLC 2012.

Authors
Voora, D; Ortel, TL; Lucas, JE; Chi, JT; Becker, RC; Ginsburg, GS
MLA Citation
Voora, D, Ortel, TL, Lucas, JE, Chi, JT, Becker, RC, and Ginsburg, GS. "Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy." Journal of Thrombosis and Thrombolysis 33.3 (2012): 246-257.
Source
scival
Published In
Journal of Thrombosis and Thrombolysis
Volume
33
Issue
3
Publish Date
2012
Start Page
246
End Page
257
DOI
10.1007/s11239-012-0683-0

Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism.

INTRODUCTION: Venous thromboembolism may recur in up to 30% of patients with a spontaneous venous thromboembolism after a standard course of anticoagulation. Identification of patients at risk for recurrent venous thromboembolism would facilitate decisions concerning the duration of anticoagulant therapy. OBJECTIVES: In this exploratory study, we investigated whether whole blood gene expression data could distinguish subjects with single venous thromboembolism from subjects with recurrent venous thromboembolism. METHODS: 40 adults with venous thromboembolism (23 with single event and 17 with recurrent events) on warfarin were recruited. Individuals with antiphospholipid syndrome or cancer were excluded. Plasma and serum samples were collected for biomarker testing, and PAXgene tubes were used to collect whole blood RNA samples. RESULTS: D-dimer levels were significantly higher in patients with recurrent venous thromboembolism, but P-selectin and thrombin-antithrombin complex levels were similar in the two groups. Comparison of gene expression data from the two groups provided us with a 50 gene probe model that distinguished these two groups with good receiver operating curve characteristics (AUC 0.75). This model includes genes involved in mRNA splicing and platelet aggregation. Pathway analysis between subjects with single and recurrent venous thromboembolism revealed that the Akt pathway was up-regulated in the recurrent venous thromboembolism group compared to the single venous thromboembolism group. CONCLUSIONS: In this exploratory study, gene expression profiles of whole blood appear to be a useful strategy to distinguish subjects with single venous thromboembolism from those with recurrent venous thromboembolism. Prospective studies with additional patients are needed to validate these results.

Authors
Lewis, DA; Stashenko, GJ; Akay, OM; Price, LI; Owzar, K; Ginsburg, GS; Chi, J-T; Ortel, TL
MLA Citation
Lewis, DA, Stashenko, GJ, Akay, OM, Price, LI, Owzar, K, Ginsburg, GS, Chi, J-T, and Ortel, TL. "Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism." Thromb Res 128.6 (December 2011): 536-540.
PMID
21737128
Source
pubmed
Published In
Thrombosis Research
Volume
128
Issue
6
Publish Date
2011
Start Page
536
End Page
540
DOI
10.1016/j.thromres.2011.06.003

Polysome profiling of the malaria parasite Plasmodium falciparum.

In the malaria parasite Plasmodium falciparum, global studies of translational regulation have been hampered by the inability to isolate malaria polysomes. We describe here a novel method for polysome profiling in P. falciparum, a powerful approach which allows both a global view of translation and the measurement of ribosomal loading and density for specific mRNAs. Simultaneous lysis of infected erythrocytes and parasites releases stable, intact malaria polysomes, which are then purified by centrifugation through a sucrose cushion. The polysomes are resuspended, separated by velocity sedimentation and then fractionated, yielding a characteristic polysome profile reflecting the global level of translational activity in the parasite. RNA isolated from specific fractions can be used to determine the density of ribosomes loaded onto a particular transcript of interest, and is free of host ribosome contamination. Thus, our approach opens translational regulation in malaria to genome-wide analysis.

Authors
Lacsina, JR; LaMonte, G; Nicchitta, CV; Chi, J-T
MLA Citation
Lacsina, JR, LaMonte, G, Nicchitta, CV, and Chi, J-T. "Polysome profiling of the malaria parasite Plasmodium falciparum." Mol Biochem Parasitol 179.1 (September 2011): 42-46.
PMID
21605599
Source
pubmed
Published In
Molecular and Biochemical Parasitology
Volume
179
Issue
1
Publish Date
2011
Start Page
42
End Page
46
DOI
10.1016/j.molbiopara.2011.05.003

Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia.

Although significant variations in the metabolic profiles exist among different cells, little is understood in terms of genetic regulations of such cell type-specific metabolic phenotypes and nutrient requirements. While many cancer cells depend on exogenous glutamine for survival to justify the therapeutic targeting of glutamine metabolism, the mechanisms of glutamine dependence and likely response and resistance of such glutamine-targeting strategies among cancers are largely unknown. In this study, we have found a systematic variation in the glutamine dependence among breast tumor subtypes associated with mammary differentiation: basal- but not luminal-type breast cells are more glutamine-dependent and may be susceptible to glutamine-targeting therapeutics. Glutamine independence of luminal-type cells is associated mechanistically with lineage-specific expression of glutamine synthetase (GS). Luminal cells can also rescue basal cells in co-culture without glutamine, indicating a potential for glutamine symbiosis within breast ducts. The luminal-specific expression of GS is directly induced by GATA3 and represses glutaminase expression. Such distinct glutamine dependency and metabolic symbiosis is coupled with the acquisition of the GS and glutamine independence during the mammary differentiation program. Understanding the genetic circuitry governing distinct metabolic patterns is relevant to many symbiotic relationships among different cells and organisms. In addition, the ability of GS to predict patterns of glutamine metabolism and dependency among tumors is also crucial in the rational design and application of glutamine and other metabolic pathway targeted therapies.

Authors
Kung, H-N; Marks, JR; Chi, J-T
MLA Citation
Kung, H-N, Marks, JR, and Chi, J-T. "Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia." PLoS Genet 7.8 (August 2011): e1002229-.
PMID
21852960
Source
pubmed
Published In
PLoS genetics
Volume
7
Issue
8
Publish Date
2011
Start Page
e1002229
DOI
10.1371/journal.pgen.1002229

Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes.

INTRODUCTION: Breast cancer heterogeneity occurs as a consequence of the dysregulation of numerous oncogenic pathways as well as many non-genetic factors, including tumor microenvironmental stresses such as hypoxia, lactic acidosis, and glucose deprivation. Although the importance of these non-genetic factors is well recognized, it is not clear how to integrate these factors within the genetic framework of cancer as the next logical step in understanding tumor heterogeneity. METHODS: We report here the development of a series of gene expression signatures to measure the influences of microenvironmental stresses. The pathway activities of hypoxia, lactic acidosis, acidosis and glucose deprivation were investigated in a collection of 1,143 breast tumors, which have been separated into 17 breast tumor subgroups defined by their distinct patterns of oncogenic pathways. A validation dataset comprised of 547 breast tumors was also used to confirm the major findings, and representative breast cancer cell lines were utilized to validate in silico results and mechanistic studies. RESULTS: Through the integrative pathway analysis of microenvironmental stresses and oncogenic events in breast tumors, we identified many known and novel correlations between these two sources of tumor heterogeneity. Focusing on differences between two human epidermal growth factor receptor 2 (HER2)-related subgroups, previously identified based on patterns of oncogenic pathway activity, we determined that these subgroups differ with regards to tumor microenvironmental signatures, including hypoxia. We further demonstrate that each of these subgroups have features consistent with basal and luminal breast tumors including patterns of oncogenic signaling pathways, expression of subtype specific genes, and cellular mechanisms that regulate the hypoxia response. Importantly, we also demonstrate that the correlated pattern of hypoxia-related gene expression and basal-associated gene expression are consistent across HER2-related tumors whether we analyze the tumors as a function of our pathway-based classification scheme, using the intrinsic gene list (ERBB2+), or based on HER2 IHC status. Our results demonstrate a cell lineage-specific phenomenon in which basal-like tumors, HER2-related tumors with high hypoxia, as well as normal basal epithelial cells express increased mRNA levels of HIF-1α compared to luminal types and silencing of HIF-1α results in decreased expression of hypoxia-induced genes. CONCLUSIONS: This study demonstrates differences in microenvironmental conditions in HER2-related subgroups defined by distinct oncogenic pathway activities, and provides a mechanistic explanation for differences in the observed hypoxia response between these subgroups. Collectively, these data demonstrate the potential of a pathway-based classification strategy as a framework to integrate genetic and non-genetic factors to investigate the basis of tumor heterogeneity.

Authors
Gatza, ML; Kung, H-N; Blackwell, KL; Dewhirst, MW; Marks, JR; Chi, J-T
MLA Citation
Gatza, ML, Kung, H-N, Blackwell, KL, Dewhirst, MW, Marks, JR, and Chi, J-T. "Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes. (Published online)" Breast Cancer Res 13.3 (June 7, 2011): R62-.
PMID
21672245
Source
pubmed
Published In
Breast Cancer Research
Volume
13
Issue
3
Publish Date
2011
Start Page
R62
DOI
10.1186/bcr2899

Comparison of genomics and functional imaging from canine sarcomas treated with thermoradiotherapy predicts therapeutic response and identifies combination therapeutics.

PURPOSE: While hyperthermia is an effective adjuvant treatment to radiotherapy, we do not completely understand the nature of the response heterogeneity. EXPERIMENTAL DESIGN: We performed gene expression analysis of 22 spontaneous canine sarcomas before and after the first hyperthermia treatment administered as an adjuvant to radiotherapy. In parallel, diffusion-weighted MRI (DWI) was done prior to the treatment course and at the end of therapy. RESULTS: From the integrative analysis of gene expression and DWI, we identified significant correlation between tumor responses with genes involved in VEGF signaling, telomerase, DNA repair, and inflammation. The treatment-induced changes in gene expression identified 2 distinct tumor subtypes with significant differences in their gene expression and treatment response, as defined by changes in DWI. The 2 tumor subtypes could also be readily identified by pretreatment gene expression. The tumor subtypes, with stronger expression response and DWI increase, had higher levels of HSP70, POT1, and centrosomal proteins, and lower levels of CD31, vWF, and transferrin. Such differential gene expression between the 2 subtypes was used to interrogate connectivity map and identify linkages to an HSP90 inhibitor, geldanamycin. We further validated the ability of geldanamycin to enhance cell killing of human tumor cells with hyperthermia and radiotherapy in clonogenic assays. CONCLUSIONS: To our knowledge, this is one of the first successful attempts to link changes in gene expression and functional imaging to understand the response heterogeneity and identify compounds enhancing thermoradiotherapy. This study also demonstrates the value of canine tumors to provide information generalizable to human tumors.

Authors
Chi, J-T; Thrall, DE; Jiang, C; Snyder, S; Fels, D; Landon, C; McCall, L; Lan, L; Hauck, M; MacFall, JR; Viglianti, BL; Dewhirst, MW
MLA Citation
Chi, J-T, Thrall, DE, Jiang, C, Snyder, S, Fels, D, Landon, C, McCall, L, Lan, L, Hauck, M, MacFall, JR, Viglianti, BL, and Dewhirst, MW. "Comparison of genomics and functional imaging from canine sarcomas treated with thermoradiotherapy predicts therapeutic response and identifies combination therapeutics." Clin Cancer Res 17.8 (April 15, 2011): 2549-2560.
PMID
21292819
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
8
Publish Date
2011
Start Page
2549
End Page
2560
DOI
10.1158/1078-0432.CCR-10-2583

Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality

Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [18F] fluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.

Authors
Chan, DA; Sutphin, PD; Nguyen, P; Turcotte, S; Lai, EW; Banh, A; Reynolds, GE; Chi, J-T; Wu, J; Solow-Cordero, DE; Bonnet, M; Flanagan, JU; Bouley, DM; Graves, EE; Denny, WA; Hay, MP; Giaccia, AJ
MLA Citation
Chan, DA, Sutphin, PD, Nguyen, P, Turcotte, S, Lai, EW, Banh, A, Reynolds, GE, Chi, J-T, Wu, J, Solow-Cordero, DE, Bonnet, M, Flanagan, JU, Bouley, DM, Graves, EE, Denny, WA, Hay, MP, and Giaccia, AJ. "Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality." Science Translational Medicine 3.94 (2011).
PMID
21813754
Source
scival
Published In
Science Translational Medicine
Volume
3
Issue
94
Publish Date
2011
DOI
10.1126/scitranslmed.3002394

Glomeruloid microvascular proliferation is associated with lack of response to chemotherapy in breast cancer

Background:Glomeruloid microvascular proliferation (GMP), a novel histology-based angiogenesis marker, has been associated with decreased survival in several human cancers.Methods:In this study, we evaluated the ability of GMP to predict clinical response to neoadjuvant chemotherapy in a series of locally advanced breast cancers (n112).Results:Presence of GMP (21% of the cases) was significantly associated with high-grade tumours and TP53 mutations in addition to the basal-like and HER2 subtypes of breast cancer as defined by gene expression data. GMP was correlated to a gene expression signature for tumour hypoxia response. The GMP pattern was also significantly associated with lack of treatment response and progressive disease (P0.004).Interpretation:The findings suggest that GMP might be able to predict the lack of response to neoadjuvant chemotherapy in locally advanced breast cancer. Whether GMP may be an independent predictor compared with other factors including TP53 mutation status and tumour grade needs confirmation in larger studies. © 2011 Cancer Research UK All rights reserved.

Authors
Akslen, LA; Straume, O; Geisler, S; Sørlie, T; Chi, J-T; Aas, T; Børresen-Dale, A-L; Lønning, PE
MLA Citation
Akslen, LA, Straume, O, Geisler, S, Sørlie, T, Chi, J-T, Aas, T, Børresen-Dale, A-L, and Lønning, PE. "Glomeruloid microvascular proliferation is associated with lack of response to chemotherapy in breast cancer." British Journal of Cancer 105.1 (2011): 9-12.
PMID
21673677
Source
scival
Published In
British Journal of Cancer
Volume
105
Issue
1
Publish Date
2011
Start Page
9
End Page
12
DOI
10.1038/bjc.2011.203

microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease.

Although individuals with homozygous sickle cell disease (HbSS) share the same genetic mutation, the severity and manifestations of this disease are extremely heterogeneous. We have previously shown that the microRNA expression in normal and HbSS erythrocytes exhibit dramatic differences. In this study, we identify a subset of HbSS patients with higher erythrocytic miR-144 expression and more severe anemia. HbSS erythrocytes are known to have reduced tolerance for oxidative stress, yet the basis for this phenotype remains unknown. This study reveals that miR-144 directly regulates nuclear factor-erythroid 2-related factor 2, a central regulator of cellular response to oxidative stress, and modulates the oxidative stress response in K562 cell line and primary erythroid progenitor cells. We further demonstrate that increased miR-144 is associated with reduced NRF2 levels in HbSS reticulocytes and with decreased glutathione regeneration and attenuated antioxidant capacity in HbSS erythrocytes, thereby providing a possible mechanism for the reduced oxidative stress tolerance and increased anemia severity seen in HbSS patients. Taken together, our findings suggest that erythroid microRNAs can serve as genetic modifiers of HbS-related anemia and can provide novel insights into the clinical heterogeneity and pathobiology of sickle cell disease.

Authors
Sangokoya, C; Telen, MJ; Chi, J-T
MLA Citation
Sangokoya, C, Telen, MJ, and Chi, J-T. "microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease." Blood 116.20 (November 18, 2010): 4338-4348.
PMID
20709907
Source
pubmed
Published In
Blood
Volume
116
Issue
20
Publish Date
2010
Start Page
4338
End Page
4348
DOI
10.1182/blood-2009-04-214817

Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA.

Although lactic acidosis is a prominent feature of solid tumors, we still have limited understanding of the mechanisms by which lactic acidosis influences metabolic phenotypes of cancer cells. We compared global transcriptional responses of breast cancer cells in response to three distinct tumor microenvironmental stresses: lactic acidosis, glucose deprivation, and hypoxia. We found that lactic acidosis and glucose deprivation trigger highly similar transcriptional responses, each inducing features of starvation response. In contrast to their comparable effects on gene expression, lactic acidosis and glucose deprivation have opposing effects on glucose uptake. This divergence of metabolic responses in the context of highly similar transcriptional responses allows the identification of a small subset of genes that are regulated in opposite directions by these two conditions. Among these selected genes, TXNIP and its paralogue ARRDC4 are both induced under lactic acidosis and repressed with glucose deprivation. This induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA:Mlx, which is usually triggered upon glucose exposure. Therefore, the upregulation of TXNIP significantly contributes to inhibition of tumor glycolytic phenotypes under lactic acidosis. Expression levels of TXNIP and ARRDC4 in human cancers are also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes. Lactic acidosis triggers features of starvation response while activating the glucose-sensing MondoA-TXNIP pathways and contributing to the "anti-Warburg" metabolic effects and anti-tumor properties of cancer cells. These results stem from integrative analysis of transcriptome and metabolic response data under various tumor microenvironmental stresses and open new paths to explore how these stresses influence phenotypic and metabolic adaptations in human cancers.

Authors
Chen, JL-Y; Merl, D; Peterson, CW; Wu, J; Liu, PY; Yin, H; Muoio, DM; Ayer, DE; West, M; Chi, J-T
MLA Citation
Chen, JL-Y, Merl, D, Peterson, CW, Wu, J, Liu, PY, Yin, H, Muoio, DM, Ayer, DE, West, M, and Chi, J-T. "Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA. (Published online)" PLoS Genet 6.9 (September 2, 2010): e1001093-.
Website
http://hdl.handle.net/10161/4477
PMID
20844768
Source
pubmed
Published In
PLoS genetics
Volume
6
Issue
9
Publish Date
2010
Start Page
e1001093
DOI
10.1371/journal.pgen.1001093

Latent factor analysis to discover pathway-associated putative segmental aneuploidies in human cancers.

Tumor microenvironmental stresses, such as hypoxia and lactic acidosis, play important roles in tumor progression. Although gene signatures reflecting the influence of these stresses are powerful approaches to link expression with phenotypes, they do not fully reflect the complexity of human cancers. Here, we describe the use of latent factor models to further dissect the stress gene signatures in a breast cancer expression dataset. The genes in these latent factors are coordinately expressed in tumors and depict distinct, interacting components of the biological processes. The genes in several latent factors are highly enriched in chromosomal locations. When these factors are analyzed in independent datasets with gene expression and array CGH data, the expression values of these factors are highly correlated with copy number alterations (CNAs) of the corresponding BAC clones in both the cell lines and tumors. Therefore, variation in the expression of these pathway-associated factors is at least partially caused by variation in gene dosage and CNAs among breast cancers. We have also found the expression of two latent factors without any chromosomal enrichment is highly associated with 12q CNA, likely an instance of "trans"-variations in which CNA leads to the variations in gene expression outside of the CNA region. In addition, we have found that factor 26 (1q CNA) is negatively correlated with HIF-1alpha protein and hypoxia pathways in breast tumors and cell lines. This agrees with, and for the first time links, known good prognosis associated with both a low hypoxia signature and the presence of CNA in this region. Taken together, these results suggest the possibility that tumor segmental aneuploidy makes significant contributions to variation in the lactic acidosis/hypoxia gene signatures in human cancers and demonstrate that latent factor analysis is a powerful means to uncover such a linkage.

Authors
Lucas, JE; Kung, H-N; Chi, J-TA
MLA Citation
Lucas, JE, Kung, H-N, and Chi, J-TA. "Latent factor analysis to discover pathway-associated putative segmental aneuploidies in human cancers. (Published online)" PLoS Comput Biol 6.9 (September 2, 2010): e1000920-.
Website
http://hdl.handle.net/10161/4453
PMID
20824128
Source
pubmed
Published In
PLoS computational biology
Volume
6
Issue
9
Publish Date
2010
Start Page
e1000920
DOI
10.1371/journal.pcbi.1000920

Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells.

Hematopoietic stem cell (HSC) self-renewal is regulated by both intrinsic and extrinsic signals. Although some of the pathways that regulate HSC self-renewal have been uncovered, it remains largely unknown whether these pathways can be triggered by deliverable growth factors to induce HSC growth or regeneration. Here we show that pleiotrophin, a neurite outgrowth factor with no known function in hematopoiesis, efficiently promotes HSC expansion in vitro and HSC regeneration in vivo. Treatment of mouse bone marrow HSCs with pleiotrophin caused a marked increase in long-term repopulating HSC numbers in culture, as measured in competitive repopulating assays. Treatment of human cord blood CD34(+)CDCD38(-)Lin(-) cells with pleiotrophin also substantially increased severe combined immunodeficient (SCID)-repopulating cell counts in culture, compared to input and cytokine-treated cultures. Systemic administration of pleiotrophin to irradiated mice caused a pronounced expansion of bone marrow stem and progenitor cells in vivo, indicating that pleiotrophin is a regenerative growth factor for HSCs. Mechanistically, pleiotrophin activated phosphoinositide 3-kinase (PI3K) signaling in HSCs; antagonism of PI3K or Notch signaling inhibited pleiotrophin-mediated expansion of HSCs in culture. We identify the secreted growth factor pleiotrophin as a new regulator of both HSC expansion and regeneration.

Authors
Himburg, HA; Muramoto, GG; Daher, P; Meadows, SK; Russell, JL; Doan, P; Chi, J-T; Salter, AB; Lento, WE; Reya, T; Chao, NJ; Chute, JP
MLA Citation
Himburg, HA, Muramoto, GG, Daher, P, Meadows, SK, Russell, JL, Doan, P, Chi, J-T, Salter, AB, Lento, WE, Reya, T, Chao, NJ, and Chute, JP. "Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells." Nat Med 16.4 (April 2010): 475-482.
PMID
20305662
Source
pubmed
Published In
Nature Medicine
Volume
16
Issue
4
Publish Date
2010
Start Page
475
End Page
482
DOI
10.1038/nm.2119

Isolation and characterization of microRNAs of human mature erythrocytes.

Human mature erythrocytes are terminally differentiated cells that have lost their nuclei and organelles during development. Even though mature erythrocytes lack ribosomal and other large-sized RNAs, they still retain small-sized RNAs. We have recently shown that there are abundant and diverse species of microRNAs in mature erythrocytes through the use of several different techniques, including northern blot, miRNA microarray, and real-time PCR. Furthermore, fractionation and genomic analysis has revealed that erythrocyte microRNA expression is different from that of reticulocytes or leukocytes and that mature erythrocytes contribute the majority of microRNA expression in whole blood. Therefore, global analysis of microRNA expression in circulating erythrocytes has the potential to provide mechanistic insights into erythrocyte biology and erythrocyte-related disorders. Here, we have provided the detailed methods for isolating and characterizing the microRNAs from human mature erythrocytes to enable such researches into human diseases involving erythrocytes.

Authors
Sangokoya, C; LaMonte, G; Chi, J-T
MLA Citation
Sangokoya, C, LaMonte, G, and Chi, J-T. "Isolation and characterization of microRNAs of human mature erythrocytes." Methods in molecular biology (Clifton, N.J.) 667 (2010): 193-203.
PMID
20827535
Source
scival
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
667
Publish Date
2010
Start Page
193
End Page
203
DOI
10.1007/978-1-60761-811-9_13

Cross-study projections of genomic biomarkers: An evaluation in cancer genomics

Human disease studies using DNA microarrays in both clinical/ observational and experimental/controlled studies are having increasing impact on our understanding of the complexity of human diseases. A fundamental concept is the use of gene expression as a "common currency" that links the results of in vitro controlled experiments to in vivo observational human studies. Many studies - in cancer and other diseases - have shown promise in using in vitro cell manipulations to improve understanding of in vivo biology, but experiments often simply fail to reflect the enormous phenotypic variation seen in human diseases. We address this with a framework and methods to dissect, enhance and extend the in vivo utility of in vitro derived gene expression signatures. From an experimentally defined gene expression signature we use statistical factor analysis to generate multiple quantitative factors in human cancer gene expression data. These factors retain their relationship to the original, one-dimensional in vitro signature but better describe the diversity of in vivo biology. In a breast cancer analysis, we show that factors can reflect fundamentally different biological processes linked to molecular and clinical features of human cancers, and that in combination they can improve prediction of clinical outcomes. © 2009 Lucas et al.

Authors
Lucas, JE; Carvalho, CM; Chen, JLY; Chi, JT; West, M
MLA Citation
Lucas, JE, Carvalho, CM, Chen, JLY, Chi, JT, and West, M. "Cross-study projections of genomic biomarkers: An evaluation in cancer genomics." PLoS ONE 4.2 (February 19, 2009).
Source
scopus
Published In
PloS one
Volume
4
Issue
2
Publish Date
2009
DOI
10.1371/journal.pone.0004523

Cross-study projections of genomic biomarkers: an evaluation in cancer genomics.

Human disease studies using DNA microarrays in both clinical/observational and experimental/controlled studies are having increasing impact on our understanding of the complexity of human diseases. A fundamental concept is the use of gene expression as a "common currency" that links the results of in vitro controlled experiments to in vivo observational human studies. Many studies--in cancer and other diseases--have shown promise in using in vitro cell manipulations to improve understanding of in vivo biology, but experiments often simply fail to reflect the enormous phenotypic variation seen in human diseases. We address this with a framework and methods to dissect, enhance and extend the in vivo utility of in vitro derived gene expression signatures. From an experimentally defined gene expression signature we use statistical factor analysis to generate multiple quantitative factors in human cancer gene expression data. These factors retain their relationship to the original, one-dimensional in vitro signature but better describe the diversity of in vivo biology. In a breast cancer analysis, we show that factors can reflect fundamentally different biological processes linked to molecular and clinical features of human cancers, and that in combination they can improve prediction of clinical outcomes.

Authors
Lucas, JE; Carvalho, CM; Chen, JL-Y; Chi, J-T; West, M
MLA Citation
Lucas, JE, Carvalho, CM, Chen, JL-Y, Chi, J-T, and West, M. "Cross-study projections of genomic biomarkers: an evaluation in cancer genomics." PLoS One 4.2 (2009): e4523-.
PMID
19225561
Source
pubmed
Published In
PloS one
Volume
4
Issue
2
Publish Date
2009
Start Page
e4523
DOI
10.1371/journal.pone.0004523

AN INTEGRATIVE ANALYSIS OF CANCER GENE EXPRESSION STUDIES USING BAYESIAN LATENT FACTOR MODELING.

We present an applied study in cancer genomics for integrating data and inferences from laboratory experiments on cancer cell lines with observational data obtained from human breast cancer studies. The biological focus is on improving understanding of transcriptional responses of tumors to changes in the pH level of the cellular microenvironment. The statistical focus is on connecting experimentally defined biomarkers of such responses to clinical outcome in observational studies of breast cancer patients. Our analysis exemplifies a general strategy for accomplishing this kind of integration across contexts. The statistical methodologies employed here draw heavily on Bayesian sparse factor models for identifying, modularizing and correlating with clinical outcome these signatures of aggregate changes in gene expression. By projecting patterns of biological response linked to specific experimental interventions into observational studies where such responses may be evidenced via variation in gene expression across samples, we are able to define biomarkers of clinically relevant physiological states and outcomes that are rooted in the biology of the original experiment. Through this approach we identify microenvironment-related prognostic factors capable of predicting long term survival in two independent breast cancer datasets. These results suggest possible directions for future laboratory studies, as well as indicate the potential for therapeutic advances though targeted disruption of specific pathway components.

Authors
Merl, D; Chen, JL-Y; Chi, J-T; West, M
MLA Citation
Merl, D, Chen, JL-Y, Chi, J-T, and West, M. "AN INTEGRATIVE ANALYSIS OF CANCER GENE EXPRESSION STUDIES USING BAYESIAN LATENT FACTOR MODELING." Ann Appl Stat 3.4 (2009): 1675-1694.
PMID
20953268
Source
pubmed
Published In
The annals of applied statistics
Volume
3
Issue
4
Publish Date
2009
Start Page
1675
End Page
1694

p38γ mitogen-activated protein kinase is a key regulator in skeletal muscle metabolic adaptation in mice

Regular endurance exercise induces skeletal muscle contractile and metabolic adaptations, conferring salutary health benefits, such as protection against the metabolic syndrome. The plasticity of skeletal muscle has been extensively investigated, but how the adaptive processes are precisely controlled is largely unknown. Using muscle-specific gene deletion in mice, we now show that p38γ mitogen-activated protein kinase (MAPK), but not p38α and p38β, is required for endurance exercise-induced mitochondrial biogenesis and angiogenesis, whereas none of the p38 isoforms are required for IIb-to-IIa fiber-type transformation. These phenotypic findings were further supported by microarray and real-time PCR analyses revealing contractile activity-dependent p38γ target genes, including peroxisome proliferator-activated receptor γ co-activator-1α (Pgc-1α) and vascular endothelial growth factor (Vegf), in skeletal muscle following motor nerve stimulation. Gene transfer-mediated overexpression of a dominant negative form of p38γ, but not that of p38α or p38β, blocked motor nerve stimulation-induced Pgc-1α transcription. These findings provide direct evidence for an obligated role of p38γ MAPK-PGC-1α regulatory axis in endurance exercise-induced metabolic adaptation, but not contractile adaptation, in skeletal muscle. © 2009 Pogozelski et al.

Authors
Pogozelski, AR; Geng, T; Li, P; Yin, X; Lira, VA; Zhang, M; Chi, J-T; Yan, Z
MLA Citation
Pogozelski, AR, Geng, T, Li, P, Yin, X, Lira, VA, Zhang, M, Chi, J-T, and Yan, Z. "p38γ mitogen-activated protein kinase is a key regulator in skeletal muscle metabolic adaptation in mice." PLoS ONE 4.11 (2009).
PMID
19936205
Source
scival
Published In
PloS one
Volume
4
Issue
11
Publish Date
2009
DOI
10.1371/journal.pone.0007934

Tumor Vasculature Is Regulated by PHD2-Mediated Angiogenesis and Bone Marrow-Derived Cell Recruitment

Sustained angiogenesis, through either local sprouting (angiogenesis) or the recruitment of bone marrow-derived cells (BMDCs) (vasculogenesis), is essential to the development of a tumor. How BMDCs are recruited to the tumor and their contribution to the tumor vasculature is poorly understood. Here, we demonstrate that both IL-8 and angiogenin contribute to the complementary pathways of angiogenesis and BMDC mobilization to increase tumor growth. These two factors are regulated by PHD2 in a HIF-independent but NF-κB-dependent manner. PHD2 levels are decreased in human cancers, compared with corresponding normal tissue, and correlate with an increase in mature blood vessels. Thus, PHD2 plays a critical role in regulating tumor angiogenesis. © 2009 Elsevier Inc. All rights reserved.

Authors
Chan, DA; Kawahara, TLA; Sutphin, PD; Chang, HY; Chi, J-T; Giaccia, AJ
MLA Citation
Chan, DA, Kawahara, TLA, Sutphin, PD, Chang, HY, Chi, J-T, and Giaccia, AJ. "Tumor Vasculature Is Regulated by PHD2-Mediated Angiogenesis and Bone Marrow-Derived Cell Recruitment." Cancer Cell 15.6 (2009): 527-538.
PMID
19477431
Source
scival
Published In
Cancer Cell
Volume
15
Issue
6
Publish Date
2009
Start Page
527
End Page
538
DOI
10.1016/j.ccr.2009.04.010

The genomic analysis of lactic acidosis and acidosis response in human cancers.

The tumor microenvironment has a significant impact on tumor development. Two important determinants in this environment are hypoxia and lactic acidosis. Although lactic acidosis has long been recognized as an important factor in cancer, relatively little is known about how cells respond to lactic acidosis and how that response relates to cancer phenotypes. We develop genome-scale gene expression studies to dissect transcriptional responses of primary human mammary epithelial cells to lactic acidosis and hypoxia in vitro and to explore how they are linked to clinical tumor phenotypes in vivo. The resulting experimental signatures of responses to lactic acidosis and hypoxia are evaluated in a heterogeneous set of breast cancer datasets. A strong lactic acidosis response signature identifies a subgroup of low-risk breast cancer patients having distinct metabolic profiles suggestive of a preference for aerobic respiration. The association of lactic acidosis response with good survival outcomes may relate to the role of lactic acidosis in directing energy generation toward aerobic respiration and utilization of other energy sources via inhibition of glycolysis. This "inhibition of glycolysis" phenotype in tumors is likely caused by the repression of glycolysis gene expression and Akt inhibition. Our study presents a genomic evaluation of the prognostic information of a lactic acidosis response independent of the hypoxic response. Our results identify causal roles of lactic acidosis in metabolic reprogramming, and the direct functional consequence of lactic acidosis pathway activity on cellular responses and tumor development. The study also demonstrates the utility of genomic analysis that maps expression-based findings from in vitro experiments to human samples to assess links to in vivo clinical phenotypes.

Authors
Chen, JL-Y; Lucas, JE; Schroeder, T; Mori, S; Wu, J; Nevins, J; Dewhirst, M; West, M; Chi, J-T
MLA Citation
Chen, JL-Y, Lucas, JE, Schroeder, T, Mori, S, Wu, J, Nevins, J, Dewhirst, M, West, M, and Chi, J-T. "The genomic analysis of lactic acidosis and acidosis response in human cancers." PLoS Genet 4.12 (December 2008): e1000293-.
PMID
19057672
Source
pubmed
Published In
PLoS genetics
Volume
4
Issue
12
Publish Date
2008
Start Page
e1000293
DOI
10.1371/journal.pgen.1000293

The genomic analysis of erythrocyte microRNA expression in sickle cell diseases.

BACKGROUND: Since mature erythrocytes are terminally differentiated cells without nuclei and organelles, it is commonly thought that they do not contain nucleic acids. In this study, we have re-examined this issue by analyzing the transcriptome of a purified population of human mature erythrocytes from individuals with normal hemoglobin (HbAA) and homozygous sickle cell disease (HbSS). METHODS AND FINDINGS: Using a combination of microarray analysis, real-time RT-PCR and Northern blots, we found that mature erythrocytes, while lacking ribosomal and large-sized RNAs, contain abundant and diverse microRNAs. MicroRNA expression of erythrocytes was different from that of reticulocytes and leukocytes, and contributed the majority of the microRNA expression in whole blood. When we used microRNA microarrays to analyze erythrocytes from HbAA and HbSS individuals, we noted a dramatic difference in their microRNA expression pattern. We found that miR-320 played an important role for the down-regulation of its target gene, CD71 during reticulocyte terminal differentiation. Further investigation revealed that poor expression of miR-320 in HbSS cells was associated with their defective downregulation CD71 during terminal differentiation. CONCLUSIONS: In summary, we have discovered significant microRNA expression in human mature erythrocytes, which is dramatically altered in HbSS erythrocytes and their defect in terminal differentiation. Thus, the global analysis of microRNA expression in circulating erythrocytes can provide mechanistic insights into the disease phenotypes of erythrocyte diseases.

Authors
Chen, S-Y; Wang, Y; Telen, MJ; Chi, J-T
MLA Citation
Chen, S-Y, Wang, Y, Telen, MJ, and Chi, J-T. "The genomic analysis of erythrocyte microRNA expression in sickle cell diseases. (Published online)" PLoS One 3.6 (June 4, 2008): e2360-.
Website
http://hdl.handle.net/10161/4495
PMID
18523662
Source
pubmed
Published In
PloS one
Volume
3
Issue
6
Publish Date
2008
Start Page
e2360
DOI
10.1371/journal.pone.0002360

Modeling cancer progression via pathway dependencies.

Cancer is a heterogeneous disease often requiring a complexity of alterations to drive a normal cell to a malignancy and ultimately to a metastatic state. Certain genetic perturbations have been implicated for initiation and progression. However, to a great extent, underlying mechanisms often remain elusive. These genetic perturbations are most likely reflected by the altered expression of sets of genes or pathways, rather than individual genes, thus creating a need for models of deregulation of pathways to help provide an understanding of the mechanisms of tumorigenesis. We introduce an integrative hierarchical analysis of tumor progression that discovers which a priori defined pathways are relevant either throughout or in particular steps of progression. Pathway interaction networks are inferred for these relevant pathways over the steps in progression. This is followed by the refinement of the relevant pathways to those genes most differentially expressed in particular disease stages. The final analysis infers a gene interaction network for these refined pathways. We apply this approach to model progression in prostate cancer and melanoma, resulting in a deeper understanding of the mechanisms of tumorigenesis. Our analysis supports previous findings for the deregulation of several pathways involved in cell cycle control and proliferation in both cancer types. A novel finding of our analysis is a connection between ErbB4 and primary prostate cancer.

Authors
Edelman, EJ; Guinney, J; Chi, J-T; Febbo, PG; Mukherjee, S
MLA Citation
Edelman, EJ, Guinney, J, Chi, J-T, Febbo, PG, and Mukherjee, S. "Modeling cancer progression via pathway dependencies." PLoS Comput Biol 4.2 (February 2008): e28-.
PMID
18282083
Source
pubmed
Published In
PLoS computational biology
Volume
4
Issue
2
Publish Date
2008
Start Page
e28
DOI
10.1371/journal.pcbi.0040028

Combining biological gene expression signatures in predicting outcome in breast cancer: An alternative to supervised classification

Introduction: Gene expression profiling has been extensively used to predict outcome in breast cancer patients. We have previously reported on biological hypothesis-driven analysis of gene expression profiling data and we wished to extend this approach through the combinations of various gene signatures to improve the prediction of outcome in breast cancer. Methods: We have used gene expression data (25.000 gene probes) from a previously published study of tumours from 295 early stage breast cancer patients from the Netherlands Cancer Institute using updated follow-up. Tumours were assigned to three prognostic groups using the previously reported Wound-response and hypoxia-response signatures, and the outcome in each of these subgroups was evaluated. Results: We have assigned invasive breast carcinomas from 295 stages I and II breast cancer patients to three groups based on gene expression profiles subdivided by the wound-response signature (WS) and hypoxia-response signature (HS). These three groups are (1) quiescent WS/non-hypoxic HS; (2) activated WS/non-hypoxic HS or quiescent WS/hypoxic tumours and (3) activated WS/hypoxic HS. The overall survival at 15 years for patients with tumours in groups 1, 2 and 3 are 79%, 59% and 27%, respectively. In multivariate analysis, this signature is not only independent of clinical and pathological risk factors; it is also the strongest predictor of outcome. Compared to a previously identified 70-gene prognosis profile, obtained with supervised classification, the combination of signatures performs roughly equally well and might have additional value in the ER-negative subgroup. In the subgroup of lymph node positive patients, the combination signature outperforms the 70-gene signature in multivariate analysis. In addition, in multivariate analysis, the WS/HS combination is a stronger predictor of outcome compared to the recently reported invasiveness gene signature combined with the WS. Conclusion: A combination of biological gene expression signatures can be used to identify a powerful and independent predictor for outcome in breast cancer patients. © 2008 Elsevier Ltd.

Authors
Nuyten, DSA; Hastie, T; Chi, J-TA; Chang, HY; Vijver, MJVD
MLA Citation
Nuyten, DSA, Hastie, T, Chi, J-TA, Chang, HY, and Vijver, MJVD. "Combining biological gene expression signatures in predicting outcome in breast cancer: An alternative to supervised classification." European Journal of Cancer 44.15 (2008): 2319-2329.
PMID
18715778
Source
scival
Published In
European Journal of Cancer
Volume
44
Issue
15
Publish Date
2008
Start Page
2319
End Page
2329
DOI
10.1016/j.ejca.2008.07.015

Transcriptome Analysis

Authors
Chi, J-TA; Nevins, JR; Febbo, PG
MLA Citation
Chi, J-TA, Nevins, JR, and Febbo, PG. "Transcriptome Analysis." The Molecular Basis of Cancer (2008): 283-291.
Source
scival
Published In
The Molecular Basis of Cancer
Publish Date
2008
Start Page
283
End Page
291
DOI
10.1016/B978-141603703-3.10021-4

A viral microRNA functions as an orthologue of cellular miR-155.

All metazoan eukaryotes express microRNAs (miRNAs), roughly 22-nucleotide regulatory RNAs that can repress the expression of messenger RNAs bearing complementary sequences. Several DNA viruses also express miRNAs in infected cells, suggesting a role in viral replication and pathogenesis. Although specific viral miRNAs have been shown to autoregulate viral mRNAs or downregulate cellular mRNAs, the function of most viral miRNAs remains unknown. Here we report that the miR-K12-11 miRNA encoded by Kaposi's-sarcoma-associated herpes virus (KSHV) shows significant homology to cellular miR-155, including the entire miRNA 'seed' region. Using a range of assays, we show that expression of physiological levels of miR-K12-11 or miR-155 results in the downregulation of an extensive set of common mRNA targets, including genes with known roles in cell growth regulation. Our findings indicate that viral miR-K12-11 functions as an orthologue of cellular miR-155 and probably evolved to exploit a pre-existing gene regulatory pathway in B cells. Moreover, the known aetiological role of miR-155 in B-cell transformation suggests that miR-K12-11 may contribute to the induction of KSHV-positive B-cell tumours in infected patients.

Authors
Gottwein, E; Mukherjee, N; Sachse, C; Frenzel, C; Majoros, WH; Chi, J-TA; Braich, R; Manoharan, M; Soutschek, J; Ohler, U; Cullen, BR
MLA Citation
Gottwein, E, Mukherjee, N, Sachse, C, Frenzel, C, Majoros, WH, Chi, J-TA, Braich, R, Manoharan, M, Soutschek, J, Ohler, U, and Cullen, BR. "A viral microRNA functions as an orthologue of cellular miR-155." Nature 450.7172 (December 13, 2007): 1096-1099.
PMID
18075594
Source
pubmed
Published In
Nature
Volume
450
Issue
7172
Publish Date
2007
Start Page
1096
End Page
1099
DOI
10.1038/nature05992

Regional specialization of endothelial cells as revealed by genomic analysis

The vascular system is locally specialized to accommodate widely varying needs of individual tissues. The regional specialization of vascular structure is closely linked to the topographic differentiation of endothelial cells (ECs). The gene expression programs that characterize specific ECs define their physiological specialization and their role in the development of vascular channels and epithelial organs. Our understanding of EC regional differentiation is very limited. To assess the heterogeneity of ECs on a global scale, we used DNA microarrays to obtain the global gene expression profiles of more than 50 cultured ECs purified from 14 different anatomic locations. We found that ECs from different blood vessels and microvascular ECs from different tissues have distinct and characteristic gene expression profiles. Pervasive differences in gene expression patterns distinguish the ECs of large vessels from microvascular ECs. We identified groups of genes characteristic of arterial and venous endothelium. Hey2, the human homolog of the zebrafish gene gridlock, was expressed only in arterial ECs and could trigger arterial-specific gene expression programs when introduced into venous ECs. Several genes critical in the establishment of left-right asymmetry were expressed preferentially in venous ECs, suggesting a surprising link between vascular differentiation and body plan development. Tissue-specific expression patterns in different tissue microvascular ECs suggest they are distinct differentiated cell types that play roles in the local physiology of their respective organs and tissues. Therefore, ECs from different anatomical locations constitute many distinct, differentiated cell types that carry out unique genetic programs to specify the site-specific design and functions of blood vessels to control internal body compartmentalization, regulate the trafficking of circulating cells, and shape the vascular development. In this chapter, we discuss these findings and their implications in different aspects of vascular biology during development and vascular diseases. © 2007 Humana Press Inc.

Authors
Chi, JTA; Wang, Z; Potti, A
MLA Citation
Chi, JTA, Wang, Z, and Potti, A. "Regional specialization of endothelial cells as revealed by genomic analysis." (December 1, 2007): 123-134. (Chapter)
Source
scopus
Publish Date
2007
Start Page
123
End Page
134
DOI
10.1007/978-1-59745-328-8_9

Gene expression programs of human smooth muscle cells: tissue-specific differentiation and prognostic significance in breast cancers.

Smooth muscle is present in a wide variety of anatomical locations, such as blood vessels, various visceral organs, and hair follicles. Contraction of smooth muscle is central to functions as diverse as peristalsis, urination, respiration, and the maintenance of vascular tone. Despite the varied physiological roles of smooth muscle cells (SMCs), we possess only a limited knowledge of the heterogeneity underlying their functional and anatomic specializations. As a step toward understanding the intrinsic differences between SMCs from different anatomical locations, we used DNA microarrays to profile global gene expression patterns in 36 SMC samples from various tissues after propagation under defined conditions in cell culture. Significant variations were found between the cells isolated from blood vessels, bronchi, and visceral organs. Furthermore, pervasive differences were noted within the visceral organ subgroups that appear to reflect the distinct molecular pathways essential for organogenesis as well as those involved in organ-specific contractile and physiological properties. Finally, we sought to understand how this diversity may contribute to SMC-involving pathology. We found that a gene expression signature of the responses of vascular SMCs to serum exposure is associated with a significantly poorer prognosis in human cancers, potentially linking vascular injury response to tumor progression.

Authors
Chi, J-T; Rodriguez, EH; Wang, Z; Nuyten, DSA; Mukherjee, S; van de Rijn, M; van de Vijver, MJ; Hastie, T; Brown, PO
MLA Citation
Chi, J-T, Rodriguez, EH, Wang, Z, Nuyten, DSA, Mukherjee, S, van de Rijn, M, van de Vijver, MJ, Hastie, T, and Brown, PO. "Gene expression programs of human smooth muscle cells: tissue-specific differentiation and prognostic significance in breast cancers." PLoS Genet 3.9 (September 2007): 1770-1784.
PMID
17907811
Source
pubmed
Published In
PLoS genetics
Volume
3
Issue
9
Publish Date
2007
Start Page
1770
End Page
1784
DOI
10.1371/journal.pgen.0030164

The potential role of intrinsic hypoxia markers as prognostic variables in cancer.

Tumor hypoxia is related to tumor progression and therapy resistance, which leads to poor patient outcome. It has been suggested that measuring the hypoxic status of a tumor helps to predict patient outcome and to select more targeted treatment. However, current methods using needle electrodes or exogenous markers have limitations due to their invasiveness or necessity for preinjection. Recent studies showed that hypoxia-regulated genes could be alternatively used as endogenous hypoxia markers. This is a review of 15 hypoxia-regulated genes, including hypoxia-inducible factor-1 and its targets, and their correlation with tumor hypoxia and patient outcome from 213 studies. Though most of the studies showed significance of these genes in predicting prognosis, there was no definitive prognostic and hypoxia marker. In conclusion, this review suggests the need for further studies with standardized methods to examine gene expression, as well as the use of multiple gene expressions.

Authors
Moon, EJ; Brizel, DM; Chi, J-TA; Dewhirst, MW
MLA Citation
Moon, EJ, Brizel, DM, Chi, J-TA, and Dewhirst, MW. "The potential role of intrinsic hypoxia markers as prognostic variables in cancer." Antioxid Redox Signal 9.8 (August 2007): 1237-1294. (Review)
PMID
17571959
Source
pubmed
Published In
Antioxidants & Redox Signaling
Volume
9
Issue
8
Publish Date
2007
Start Page
1237
End Page
1294
DOI
10.1089/ars.2007.1623

Predicting a local recurrence after breast-conserving therapy by gene expression profiling

Introduction: To tailor local treatment in breast cancer patients there is a need for predicting ipsilateral recurrences after breast-conserving therapy. After adequate treatment (excision with free margins and radiotherapy), young age and incompletely excised extensive intraductal component are predictors for local recurrence, but many local recurrences can still not be predicted. Here we have used gene expression profiling by microarray analysis to identify gene expression profiles that can help to predict local recurrence in individual patients. Methods: By using previously established gene expression profiles with proven value in predicting metastasis-free and overall survival (wound-response signature, 70-gene prognosis profile and hypoxia-induced profile) and training towards an optimal prediction of local recurrences in a training series, we establish a classifier for local recurrence after breast-conserving therapy. Results: Validation of the different gene lists shows that the wound-response signature is able to separate patients with a high (29%) or low (5%) risk of a local recurrence at 10 years (sensitivity 87.5%, specificity 75%). In multivariable analysis the classifier is an independent predictor for local recurrence. Conclusion: Our findings indicate that gene expression profiling can identify subgroups of patients at increased risk of developing a local recurrence after breast-conserving therapy. © 2006 Nuyten et al.; licensee BioMed Central Ltd.

Authors
Nuyten, DSA; Kreike, B; Hart, AAM; Chi, J-TA; Sneddon, JB; Wessels, LFA; Peterse, HJ; Bartelink, H; Brown, PO; Chang, HY; Vijver, MJVD
MLA Citation
Nuyten, DSA, Kreike, B, Hart, AAM, Chi, J-TA, Sneddon, JB, Wessels, LFA, Peterse, HJ, Bartelink, H, Brown, PO, Chang, HY, and Vijver, MJVD. "Predicting a local recurrence after breast-conserving therapy by gene expression profiling." Breast Cancer Research 8.5 (2006).
PMID
17069664
Source
scival
Published In
Breast Cancer Research
Volume
8
Issue
5
Publish Date
2006
DOI
10.1186/bcr1614

Lysyl oxidase is essential for hypoxia-induced metastasis

Metastasis is a multistep process responsible for most cancer deaths, and it can be influenced by both the immediate microenvironment (cell-cell or cell-matrix interactions) and the extended tumour microenvironment (for example vascularization)1. Hypoxia (low oxygen) is clinically associated with metastasis and poor patient outcome, although the underlying processes remain unclear2. Microarray studies have shown the expression of lysyl oxidase (LOX) to be elevated in hypoxic human tumour cells3. Paradoxically, LOX expression is associated with both tumour suppression and tumour progression, and its role in tumorigenesis seems dependent on cellular location, cell type and transformation status 4-9. Here we show that LOX expression is regulated by hypoxia-inducible factor (HIF) and is associated with hypoxia in human breast and head and neck tumours. Patients with high LOX-expressing tumours have poor distant metastasis-free and overall survivals. Inhibition of LOX eliminates metastasis in mice with orthotopically grown breast cancer tumours. Mechanistically, secreted LOX is responsible for the invasive properties of hypoxic human cancer cells through focal adhesion kinase activity and cell to matrix adhesion. Furthermore, LOX may be required to create a niche permissive for metastatic growth. Our findings indicate that LOX is essential for hypoxia-induced metastasis and is a good therapeutic target for preventing and treating metastases. © 2006 Nature Publishing Group.

Authors
Erler, JT; Bennewith, KL; Nicolau, M; Dornhöfer, N; Kong, C; Le, Q-T; Chi, J-TA; Jeffrey, SS; Giaccia, AJ
MLA Citation
Erler, JT, Bennewith, KL, Nicolau, M, Dornhöfer, N, Kong, C, Le, Q-T, Chi, J-TA, Jeffrey, SS, and Giaccia, AJ. "Lysyl oxidase is essential for hypoxia-induced metastasis." Nature 440.7088 (2006): 1222-1226.
PMID
16642001
Source
scival
Published In
Nature
Volume
440
Issue
7088
Publish Date
2006
Start Page
1222
End Page
1226
DOI
10.1038/nature04695

Gene expression programs in response to hypoxia: Cell type specificity and prognostic significance in human cancers

Background: Inadequate oxygen (hypoxia) triggers a multifaceted cellular response that has important roles in normal physiology and in many human diseases. A transcription factor, hypoxia-inducible factor (HIF), plays a central role in the hypoxia response; its activity is regulated by the oxygen-dependent degradation of the HIF-1α protein. Despite the ubiquity and importance of hypoxia responses, little is known about the variation in the global transcriptional response to hypoxia among different cell types or how this variation might relate to tissue- and cell-specific diseases. Methods and Findings: We analyzed the temporal changes in global transcript levels in response to hypoxia in primary renal proximal tubule epithelial cells, breast epithelial cells, smooth muscle cells, and endothelial cells with DNA microarrays. The extent of the transcriptional response to hypoxia was greatest in the renal tubule cells. This heightened response was associated with a uniquely high level of HIF-1α RNA in renal cells, and it could be diminished by reducing HIF-1α expression via RNA interference. A gene-expression signature of the hypoxia response, derived from our studies of cultured mammary and renal tubular epithelial cells, showed coordinated variation in several human cancers, and was a strong predictor of clinical outcomes in breast and ovarian cancers. In an analysis of a large, published gene-expression dataset from breast cancers, we found that the prognostic information in the hypoxia signature was virtually independent of that provided by the previously reported wound signature and more predictive of outcomes than any of the clinical parameters in current use. Conclusions: The transcriptional response to hypoxia varies among human cells. Some of this variation is traceable to variation in expression of the HIF1A gene. A gene-expression signature of the cellular response to hypoxia is associated with a significantly poorer prognosis in breast and ovarian cancer. © 2006 Chi et al.

Authors
Chi, J-T; Wang, Z; Nuyten, DSA; Rodriguez, EH; Schaner, ME; Salim, A; Wang, Y; Kristensen, GB; Helland, Å; Børresen-Dale, A-L; Giaccia, A; Longaker, MT; Hastie, T; Yang, GP; Vijver, MJVD; Brown, PO
MLA Citation
Chi, J-T, Wang, Z, Nuyten, DSA, Rodriguez, EH, Schaner, ME, Salim, A, Wang, Y, Kristensen, GB, Helland, Å, Børresen-Dale, A-L, Giaccia, A, Longaker, MT, Hastie, T, Yang, GP, Vijver, MJVD, and Brown, PO. "Gene expression programs in response to hypoxia: Cell type specificity and prognostic significance in human cancers." PLoS Medicine 3.3 (2006): 395-409.
PMID
16417408
Source
scival
Published In
PLoS medicine
Volume
3
Issue
3
Publish Date
2006
Start Page
395
End Page
409
DOI
10.1371/journal.pmed.0030047

High-throughput RNA interference

Introduction RNA interference (RNAi) is an evolutionarily conserved pathway of gene silencing that identifies and destroys mRNA sequences derived from selfish repetitive or viral sequences. The mechanisms and physiologic functions of RNAi pathways are discussed in Section 1. Because RNAi can be triggered by exogenously supplied double-stranded RNA (dsRNA) molecules, in principle one can effectively silence the expression of a gene and infer its physiologic function given its sequence. RNAi analysis on a genome-wide scale is a versatile and powerful tool that holds great promise in functional annotation of the human genome and in acceleration of drug target discovery and validation. The rapid advances to date have illustrated that high-throughput RNAi can complement genetic studies in traditional model organisms to extend our understanding and probe the mechanisms of well-studied pathways. In this chapter, we will focus on emerging methodologies and issues surrounding high-throughput RNAi in mammalian systems, and highlight the potential advances and pitfalls with these new technologies. Generation of genome-wide RNAi reagents In order to silence each gene in the genome using RNAi, the first step is to create the appropriate library of dsRNA reagents. In Caenorhabditis elegans and Drosophila melanogaster, long segments of dsRNA are readily taken up by the animal or tissue culture cells, respectively, and genome-wide RNAi libraries can be constructed by annealing complementary RNAs synthesized from both strands of the same cDNA.

Authors
Chang, HY; Wang, NN; Chi, JT
MLA Citation
Chang, HY, Wang, NN, and Chi, JT. "High-throughput RNA interference." (January 1, 2005): 470-479. (Chapter)
Source
scopus
Publish Date
2005
Start Page
470
End Page
479
DOI
10.1017/CBO9780511546402.036

Gene expression signature of fibroblast serum response predicts human cancer progression: Similarities between tumors and wounds

Cancer invasion and metastasis have been likened to wound healing gone awry. Despite parallels in cellular behavior between cancer progression and wound healing, the molecular relationships between these two processes and their prognostic implications are unclear. In this study, based on gene expression profiles of fibroblasts from ten anatomic sites, we identify a stereotyped gene expression program in response to serum exposure that appears to reflect the multifaceted role of fibroblasts in wound healing. The genes comprising this fibroblast common serum response are coordinately regulated in many human tumors, allowing us to identify tumors with gene expression signatures suggestive of active wounds. Genes induced in the fibroblast serum-response program are expressed in tumors by the tumor cells themselves, by tumor-associated fibroblasts, or both. The molecular features that define this wound-like phenotype are evident at an early clinical stage, persist during treatment, and predict increased risk of metastasis and death in breast, lung, and gastric carcinomas. Thus, the transcriptional signature of the response of fibroblasts to serum provides a possible link between cancer progression and wound healing, as well as a powerful predictor of the clinical course in several common carcinomas.

Authors
Chang, HY; Sneddon, JB; Alizadeh, AA; Sood, R; West, RB; Montgomery, K; Chi, J-T; Rijn, MVD; Botstein, D; Brown, PO
MLA Citation
Chang, HY, Sneddon, JB, Alizadeh, AA, Sood, R, West, RB, Montgomery, K, Chi, J-T, Rijn, MVD, Botstein, D, and Brown, PO. "Gene expression signature of fibroblast serum response predicts human cancer progression: Similarities between tumors and wounds." PLoS Biology 2.2 (2004).
PMID
14737219
Source
scival
Published In
PLoS Biology
Volume
2
Issue
2
Publish Date
2004
DOI
10.1371/journal.pbio.0020007

Genomewide view of gene silencing by small interfering RNAs

RNA interference (RNAi) is an evolutionarily conserved mechanism in plant and animal cells that directs the degradation of messenger RNAs homologous to short double-stranded RNAs termed small interfering RNA (siRNA). The ability of siRNA to direct gene silencing in mammalian cells has raised the possibility that siRNA might be used to investigate gene function in a high throughput fashion or to modulate gene expression in human diseases. The specificity of siRNA-mediated silencing, a critical consideration in these applications, has not been addressed on a genomewide scale. Here we show that siRNA-induced gene silencing of transient or stably expressed mRNA is highly gene-specific and does not produce secondary effects detectable by genomewide expression profiling. A test for transitive RNAi, extension of the RNAi effect to sequences 5′ of the target region that has been observed in Caenorhabditis elegans, was unable to detect this phenomenon in human cells.

Authors
Chi, J-T; Chang, HY; Wang, NN; Chang, DS; Dunphy, N; Brown, PO
MLA Citation
Chi, J-T, Chang, HY, Wang, NN, Chang, DS, Dunphy, N, and Brown, PO. "Genomewide view of gene silencing by small interfering RNAs." Proceedings of the National Academy of Sciences of the United States of America 100.11 (2003): 6343-6346.
PMID
12730368
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
100
Issue
11
Publish Date
2003
Start Page
6343
End Page
6346
DOI
10.1073/pnas.1037853100

Endothelial cell diversity revealed by global expression profiling

The vascular system is locally specialized to accommodate widely varying blood flow and pressure and the distinct needs of individual tissues. The endothelial cells (ECs) that line the lumens of blood and lymphatic vessels play an integral role in the regional specialization of vascular structure and physiology. However, our understanding of EC diversity is limited. To explore EC specialization on a global scale, we used DNA microarrays to determine the expression profile of 53 cultured ECs. We found that ECs from different blood vessels and microvascular ECs from different tissues have distinct and characteristic gene expression profiles. Pervasive differences in gene expression patterns distinguish the ECs of large vessels from microvascular ECs. We identified groups of genes characteristic of arterial and venous endothelium. Hey2, the human homologue of the zebrafish gene gridlock, was selectively expressed in arterial ECs and induced the expression of several arterial-specific genes. Several genes critical in the establishment of left/right asymmetry were expressed preferentially in venous ECs, suggesting coordination between vascular differentiation and body plan development. Tissue-specific expression patterns in different tissue microvascular ECs suggest they are distinct differentiated cell types that play roles in the local physiology of their respective organs and tissues.

Authors
Chi, J-T; Chang, HY; Haraldsen, G; Jahnsen, FL; Troyanskaya, OG; Chang, DS; Wang, Z; Rockson, SG; Rijn, MVD; Botstein, D; Brown, PO
MLA Citation
Chi, J-T, Chang, HY, Haraldsen, G, Jahnsen, FL, Troyanskaya, OG, Chang, DS, Wang, Z, Rockson, SG, Rijn, MVD, Botstein, D, and Brown, PO. "Endothelial cell diversity revealed by global expression profiling." Proceedings of the National Academy of Sciences of the United States of America 100.19 (2003): 10623-10628.
PMID
12963823
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
100
Issue
19
Publish Date
2003
Start Page
10623
End Page
10628
DOI
10.1073/pnas.1434429100

Systemic and cell type-specific gene expression patterns in scleroderma skin

We used DNA microarrays representing >12,000 human genes to characterize gene expression patterns in skin biopsies from individuals with a diagnosis of systemic sclerosis with diffuse scleroderma. We found consistent differences in the patterns of gene expression between skin biopsies from individuals with scleroderma and those from normal, unaffected individuals. The biopsies from affected individuals showed nearly indistinguishable patterns of gene expression in clinically affected and clinically unaffected tissue, even though these were clearly distinguishable from the patterns found in similar tissue from unaffected individuals. Genes characteristically expressed in endothelial cells, B lymphocytes, and fibroblasts showed differential expression between scleroderma and normal biopsies. Analysis of lymphocyte populations in scleroderma skin biopsies by immunohistochemistry suggest the B lymphocyte signature observed on our arrays is from CD20+ B cells. These results provide evidence that scleroderma has systemic manifestations that affect multiple cell types and suggests genes that could be used as potential markers for the disease.

Authors
Whitfield, ML; Finlay, DR; Murray, JI; Troyanskaya, OG; Chi, J-T; Pergamenschikov, A; McCalmont, TH; Brown, PO; Botstein, D; Connolly, MK
MLA Citation
Whitfield, ML, Finlay, DR, Murray, JI, Troyanskaya, OG, Chi, J-T, Pergamenschikov, A, McCalmont, TH, Brown, PO, Botstein, D, and Connolly, MK. "Systemic and cell type-specific gene expression patterns in scleroderma skin." Proceedings of the National Academy of Sciences of the United States of America 100.21 (2003): 12319-12324.
PMID
14530402
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
100
Issue
21
Publish Date
2003
Start Page
12319
End Page
12324
DOI
10.1073/pnas.1635114100

Genetic susceptibility to keloid disease and hypertrophic scarring: Transforming growth factor β1 common polymorphisms and plasma levels: Discussion

Authors
Yang, GP; Chi, J-TA; Longaker, MT
MLA Citation
Yang, GP, Chi, J-TA, and Longaker, MT. "Genetic susceptibility to keloid disease and hypertrophic scarring: Transforming growth factor β1 common polymorphisms and plasma levels: Discussion." Plastic and Reconstructive Surgery 111.2 (2003): 544-546.
Source
scival
Published In
Plastic and Reconstructive Surgery
Volume
111
Issue
2
Publish Date
2003
Start Page
544
End Page
546
DOI
10.1097/01.PRS.0000041537.30632.04

Diversity, topographic differentiation, and positional memory in human fibroblasts

A fundamental feature of the architecture and functional design of vertebrate animals is a stroma, composed of extracellular matrix and mesenchymal cells, which provides a structural scaffold and conduit for blood and lymphatic vessels, nerves, and leukocytes. Reciprocal interactions between mesenchymal and epithelial cells are known to play a critical role in orchestrating the development and morphogenesis of tissues and organs, but the roles played by specific stromal cells in controlling the design and function of tissues remain poorly understood. The principal cells of stromal tissue are called fibroblasts, a catch-all designation that belies their diversity. We characterized genome-wide patterns of gene expression in cultured fetal and adult human fibroblasts derived from skin at different anatomical sites. Fibroblasts from each site displayed distinct and characteristic transcriptional patterns, suggesting that fibroblasts at different locations in the body should be considered distinct differentiated cell types. Notable groups of differentially expressed genes included some implicated in extracellular matrix synthesis, lipid metabolism, and cell signaling pathways that control proliferation, cell migration, and fate determination. Several genes implicated in genetic diseases were found to be expressed in fibroblasts in an anatomic pattern that paralleled the phenotypic defects. Finally, adult fibroblasts maintained key features of HOX gene expression patterns established during embryogenesis, suggesting that HOX genes may direct topographic differentiation and underlie the detailed positional memory in fibroblasts.

Authors
Chang, HY; Chi, J-T; Dudoit, S; Bondre, C; Rijn, MVD; Botstein, D; Brown, PO
MLA Citation
Chang, HY, Chi, J-T, Dudoit, S, Bondre, C, Rijn, MVD, Botstein, D, and Brown, PO. "Diversity, topographic differentiation, and positional memory in human fibroblasts." Proceedings of the National Academy of Sciences of the United States of America 99.20 (2002): 12877-12882.
PMID
12297622
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
99
Issue
20
Publish Date
2002
Start Page
12877
End Page
12882
DOI
10.1073/pnas.162488599

Comprehensive analysis of the gene expression profiles in human gastric cancer cell lines

Gastric adenocarcinoma is one of the major malignancies worldwide. Gastric cell lines have been widely used as the model to study the genetics, pharmacology and biochemistry of gastric cancers. Here we describe a comprehensive survey of the gene expression profiles of 12 gastric carcinoma cell lines, using cDNA microarray with 43 000 clones. For comparison, we also explored the gene expression patterns of 15 cell lines derived from lymphoid, endothelial, stromal and other epithelial cancers. Expression levels of specific genes were validated through comparison to protein expression by immunohistochemistry using cell block arrays. We found sets of genes whose expression corresponds to the molecular signature of each cell type. In the gastric cancer cell lines, apart from genes that are highly expressed corresponding to their common epithelial origin from the gastrointestinal tract, we found marked heterogeneity among the gene expression patterns of these cell lines. Some of the heterogeneity may reflect their underlying molecular characteristics or specific differentiation program. Two putative gastric carcinoma cell lines were found to be B-cell lymphoma, and another one had no epithelial specific gene expression and hence was of doubtful epithelial origin. These cell lines should no longer be used in gastric carcinoma research. In conclusion, our gene expression database can serve as a powerful resource for the study of gastric cancer using these cell lines.

Authors
Ji, J; Chen, X; Leung, SY; Chi, J-TA; Chu, KM; Yuen, ST; Li, R; Chan, AS; Li, J; Dunphy, N; So, S
MLA Citation
Ji, J, Chen, X, Leung, SY, Chi, J-TA, Chu, KM, Yuen, ST, Li, R, Chan, AS, Li, J, Dunphy, N, and So, S. "Comprehensive analysis of the gene expression profiles in human gastric cancer cell lines." Oncogene 21.42 (2002): 6549-6556.
Source
scival
Published In
Oncogene
Volume
21
Issue
42
Publish Date
2002
Start Page
6549
End Page
6556
DOI
10.1038/sj.onc.1205829

Differential effect of B lymphocyte-induced maturation protein (Blimp- 1) expression on cell fate during B cell development

The B lymphocyte-induced maturation protein (Blimp-1) upregulates the expression of syndecan-1 and J chain and represses that of c-myc. We have transfected Blimp-1 into two sublines of the BCL1 B cell lymphoma that represent distinct stages of B cell development in secondary lymphoid tissues. After interleukin (IL)-2 and IL-5 stimulation, the BCL1 3B3 cells differentiate into centrocyte-like cells, whereas the BCL1 5B1b cells blast and appear to be blocked at the centroblast stage. This blasting effect and the increase in IgM secretion that follows it can be blocked by a dominant negative form of Blimp-1. At the same time, the ectopic expression of Blimp- 1 in these partially activated cells induces an apoptotic response that also can be suppressed by the same dominant negative protein. A similar effect was noticed when Blimp-1 was expressed in the mature L10A and the immature WEHI- 231 lines, indicating this may be a general effect at earlier stages of the B cell development, and distinct from the ability of Blimp-1 to induce maturation in late stages of differentiation. Truncation mutants indicate that the induction of the apoptotic response relies mainly on 69 amino acids within Blimp-1's proline-rich domain. We propose that Blimp-1 expression defines a checkpoint beyond which fully activated B cells proceed to the plasma cell stage, whereas immature and partially activated cells are eliminated at this point.

Authors
Messika, EJ; Lu, PS; Sung, Y-J; Yao, T; Chi, J-T; Chien, Y-H; Davis, MM
MLA Citation
Messika, EJ, Lu, PS, Sung, Y-J, Yao, T, Chi, J-T, Chien, Y-H, and Davis, MM. "Differential effect of B lymphocyte-induced maturation protein (Blimp- 1) expression on cell fate during B cell development." Journal of Experimental Medicine 188.3 (1998): 515-525.
PMID
9687529
Source
scival
Published In
The Journal of Experimental Medicine
Volume
188
Issue
3
Publish Date
1998
Start Page
515
End Page
525
DOI
10.1084/jem.188.3.515
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