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Shen, Xiling

Overview:

The Shen lab uses systems biology to study spatiotemporal controls of multicellular systems, and how their subversion lead to diseases. Ongoing projects include colon cancer, normal and cancer stem cells, non-coding RNA, enteric nervious system, and tuberculosis.

Positions:

Associate Professor in the Department of Biomedical Engineering

Biomedical Engineering
Pratt School of Engineering

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.Sc. 2001

B.Sc. — Stanford University

M.Sc. 2001

M.Sc. — Stanford University

Ph.D. 2008

Ph.D. — Stanford University

News:

Grants:

A comprehensive research resource to define mechanisms underlying microbial regulation of host metabolism in pediatric obesity and obesity-targeted therapeutics

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 25, 2016
End Date
August 31, 2021

Engineering signaling specificity to program intestinal organoid development

Administered By
Biomedical Engineering
AwardedBy
Defense Advanced Research Projects Agency
Role
Principal Investigator
Start Date
October 01, 2016
End Date
September 30, 2020

Functional mapping of efferent gut neuroepithelial circuits

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 28, 2016
End Date
July 31, 2018

Robustness of the Intestinal Stem Cell Niche

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 05, 2015
End Date
February 28, 2018

Metabolic Reprogramming of Colon Cancer Liver Metastasis

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 13, 2016
End Date
December 31, 2017
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Publications:

Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma.

De novo synthesis of guanosine diphosphate (GDP)-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or tissue specific transplantation antigen P35B [TSTA3]). GMDS deletions and mutations are found in 6%-13% of colorectal cancers; these mostly affect the ascending and transverse colon. We investigated whether a lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis.FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency. We studied a mouse model of fucosylation deficiency (Fx-/- mice) and mice with the full-length Fx gene (controls). Mice were placed on standard chow or fucose-containing diet (equivalent to a control fucosylglycan phenotype). Colon tissues were collected and analyzed histologically or by enzyme-linked immunosorbent assays to measure cytokine levels; T cells also were collected and analyzed. Fecal samples were analyzed by 16s ribosomal RNA sequencing. Mucosal barrier function was measured by uptake of fluorescent dextran. We transplanted bone marrow cells from Fx-/- or control mice (Ly5.2) into irradiated 8-week-old Fx-/- or control mice (Ly5.1). We performed immunohistochemical analyses for expression of Notch and the hes family bHLH transcription factor (HES1) in colon tissues from mice and a panel of 60 human colorectal cancer specimens (27 left-sided, 33 right-sided).Fx-/- mice developed colitis and serrated-like lesions. The intestinal pathology of Fx-/- mice was reversed by addition of fucose to the diet, which restored fucosylation via a salvage pathway. In the absence of fucosylation, dysplasia appeared and progressed to adenocarcinoma in up to 40% of mice, affecting mainly the right colon and cecum. Notch was not activated in Fx-/- mice fed standard chow, leading to decreased expression of its target Hes1. Fucosylation deficiency altered the composition of the fecal microbiota, reduced mucosal barrier function, and altered epithelial proliferation marked by Ki67. Fx-/- mice receiving control bone marrow cells had intestinal inflammation and dysplasia, and reduced expression of cytokines produced by cytotoxic T cells. Human sessile serrated adenomas and right-sided colorectal tumors with epigenetic loss of MutL homolog 1 (MLH1) had lost or had lower levels of HES1 than other colorectal tumor types or nontumor tissues.In mice, fucosylation deficiency leads to colitis and adenocarcinoma, loss of Notch activation, and down-regulation of Hes1. HES1 loss correlates with the development of human right-sided colorectal tumors with epigenetic loss of MLH1. These findings indicate that carcinogenesis in a subset of colon cancer is consequent to a molecular mechanism driven by fucosylation deficiency and/or HES1-loss.

Authors
Wang, Y; Huang, D; Chen, K-Y; Cui, M; Wang, W; Huang, X; Awadellah, A; Li, Q; Friedman, A; Xin, WW; Di Martino, L; Cominelli, F; Miron, A; Chan, R; Fox, JG; Xu, Y; Shen, X; Kalady, MF; Markowitz, S; Maillard, I; Lowe, JB; Xin, W; Zhou, L
MLA Citation
Wang, Y, Huang, D, Chen, K-Y, Cui, M, Wang, W, Huang, X, Awadellah, A, Li, Q, Friedman, A, Xin, WW, Di Martino, L, Cominelli, F, Miron, A, Chan, R, Fox, JG, Xu, Y, Shen, X, Kalady, MF, Markowitz, S, Maillard, I, Lowe, JB, Xin, W, and Zhou, L. "Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma." Gastroenterology 152.1 (January 2017): 193-205.e10.
PMID
27639802
Source
epmc
Published In
Gastroenterology
Volume
152
Issue
1
Publish Date
2017
Start Page
193
End Page
205.e10
DOI
10.1053/j.gastro.2016.09.004

A recellularized human colon model identifies cancer driver genes.

Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia. We identified 38 candidate invasion-driver genes, 17 of which, including TCF7L2, TWIST2, MSH2, DCC, EPHB1 and EPHB2 have been previously implicated in colorectal cancer progression. Six invasion-driver genes that have not, to our knowledge, been previously described were validated in vitro using cell proliferation, migration and invasion assays and ex vivo using recellularized human colon. These results demonstrate the utility of our organoid model for studying cancer biology.

Authors
Chen, HJ; Wei, Z; Sun, J; Bhattacharya, A; Savage, DJ; Serda, R; Mackeyev, Y; Curley, SA; Bu, P; Wang, L; Chen, S; Cohen-Gould, L; Huang, E; Shen, X; Lipkin, SM; Copeland, NG; Jenkins, NA; Shuler, ML
MLA Citation
Chen, HJ, Wei, Z, Sun, J, Bhattacharya, A, Savage, DJ, Serda, R, Mackeyev, Y, Curley, SA, Bu, P, Wang, L, Chen, S, Cohen-Gould, L, Huang, E, Shen, X, Lipkin, SM, Copeland, NG, Jenkins, NA, and Shuler, ML. "A recellularized human colon model identifies cancer driver genes." Nature biotechnology 34.8 (August 2016): 845-851.
PMID
27398792
Source
epmc
Published In
Nature Biotechnology
Volume
34
Issue
8
Publish Date
2016
Start Page
845
End Page
851
DOI
10.1038/nbt.3586

Asymmetric division: An antitumor player?

miR-34a-mediated asymmetric cell division reins in excessive stem cell expansion during tissue regeneration in the intestine and colon. Loss of miR-34a switches asymmetric division to symmetric division and enhances stem cell proliferation. Asymmetric division also occurs in the early stages of colon cancer stem cells. Mechanistically, miR-34a, Numb, and Notch form a feed-forward loop that specifies cell fate when stem cells divide.

Authors
Wang, L; Bu, P; Shen, X
MLA Citation
Wang, L, Bu, P, and Shen, X. "Asymmetric division: An antitumor player?." Molecular & cellular oncology 3.4 (July 2016): e1164279-.
PMID
27652318
Source
epmc
Published In
Molecular & cellular oncology
Volume
3
Issue
4
Publish Date
2016
Start Page
e1164279
DOI
10.1080/23723556.2016.1164279

Simultaneous optical and electrical in vivo analysis of the enteric nervous system.

The enteric nervous system (ENS) is a major division of the nervous system and vital to the gastrointestinal (GI) tract and its communication with the rest of the body. Unlike the brain and spinal cord, relatively little is known about the ENS in part because of the inability to directly monitor its activity in live animals. Here, we integrate a transparent graphene sensor with a customized abdominal window for simultaneous optical and electrical recording of the ENS in vivo. The implanted device captures ENS responses to neurotransmitters, drugs and optogenetic manipulation in real time.

Authors
Rakhilin, N; Barth, B; Choi, J; Muñoz, NL; Kulkarni, S; Jones, JS; Small, DM; Cheng, Y-T; Cao, Y; LaVinka, C; Kan, E; Dong, X; Spencer, M; Pasricha, P; Nishimura, N; Shen, X
MLA Citation
Rakhilin, N, Barth, B, Choi, J, Muñoz, NL, Kulkarni, S, Jones, JS, Small, DM, Cheng, Y-T, Cao, Y, LaVinka, C, Kan, E, Dong, X, Spencer, M, Pasricha, P, Nishimura, N, and Shen, X. "Simultaneous optical and electrical in vivo analysis of the enteric nervous system." Nature communications 7 (June 7, 2016): 11800-.
PMID
27270085
Source
epmc
Published In
Nature Communications
Volume
7
Publish Date
2016
Start Page
11800
DOI
10.1038/ncomms11800

NOTCH Signaling Regulates Asymmetric Cell Fate of Fast- and Slow-Cycling Colon Cancer-Initiating Cells.

Colorectal cancer cells with stem-like properties, referred to as colon cancer-initiating cells (CCIC), have high tumorigenic potential. While CCIC can differentiate to promote cellular heterogeneity, it remains unclear whether CCIC within a tumor contain distinct subpopulations. Here, we describe the co-existence of fast- and slow-cycling CCIC, which can undergo asymmetric division to generate each other, highlighting CCIC plasticity and interconvertibility. Fast-cycling CCIC express markers, such as LGR5 and CD133, rely on MYC for their proliferation, whereas slow-cycling CCIC express markers, such as BMI1 and hTERT, are independent of MYC. NOTCH signaling promotes asymmetric cell fate, regulating the balance between these two populations. Overall, our results illuminate the basis for CCIC heterogeneity and plasticity by defining a direct interconversion mechanism between slow- and fast-cycling CCIC. Cancer Res; 76(11); 3411-21. ©2016 AACR.

Authors
Srinivasan, T; Walters, J; Bu, P; Than, EB; Tung, K-L; Chen, K-Y; Panarelli, N; Milsom, J; Augenlicht, L; Lipkin, SM; Shen, X
MLA Citation
Srinivasan, T, Walters, J, Bu, P, Than, EB, Tung, K-L, Chen, K-Y, Panarelli, N, Milsom, J, Augenlicht, L, Lipkin, SM, and Shen, X. "NOTCH Signaling Regulates Asymmetric Cell Fate of Fast- and Slow-Cycling Colon Cancer-Initiating Cells." Cancer research 76.11 (June 2016): 3411-3421.
PMID
27197180
Source
epmc
Published In
Cancer Research
Volume
76
Issue
11
Publish Date
2016
Start Page
3411
End Page
3421
DOI
10.1158/0008-5472.can-15-3198

The Ex Vivo Culture and Pattern Recognition Receptor Stimulation of Mouse Intestinal Organoids.

Primary intestinal organoids are a valuable model system that has the potential to significantly impact the field of mucosal immunology. However, the complexities of the organoid growth characteristics carry significant caveats for the investigator. Specifically, the growth patterns of each individual organoid are highly variable and create a heterogeneous population of epithelial cells in culture. With such caveats, common tissue culture practices cannot be simply applied to the organoid system due to the complexity of the cellular structure. Counting and plating based solely on cell number, which is common for individually separated cells, such as cell lines, is not a reliable method for organoids unless some normalization technique is applied. Normalizing to total protein content is made complex due to the resident protein matrix. These characteristics in terms of cell number, shape and cell type should be taken into consideration when evaluating secreted contents from the organoid mass. This protocol has been generated to outline a simple procedure to culture and treat small intestinal organoids with microbial pathogens and pathogen associated molecular patterns (PAMPs). It also emphasizes the normalization techniques that should be applied when protein analysis are conducted after such a challenge.

Authors
Rothschild, DE; Srinivasan, T; Aponte-Santiago, LA; Shen, X; Allen, IC
MLA Citation
Rothschild, DE, Srinivasan, T, Aponte-Santiago, LA, Shen, X, and Allen, IC. "The Ex Vivo Culture and Pattern Recognition Receptor Stimulation of Mouse Intestinal Organoids." Journal of visualized experiments : JoVE 111 (May 18, 2016).
PMID
27285214
Source
epmc
Published In
Journal of Visualized Experiments
Issue
111
Publish Date
2016
DOI
10.3791/54033

Notch signalling regulates asymmetric division and inter-conversion between lgr5 and bmi1 expressing intestinal stem cells.

Rapidly cycling LGR5+ intestinal stem cells (ISCs) located at the base of crypts are the primary driver of regeneration. Additionally, BMI1 expression is correlated with a slow cycling pool of ISCs located at +4 position. While previous reports have shown interconversion between these two populations following tissue injury, we provide evidence that NOTCH signaling regulates the balance between these two populations and promotes asymmetric division as a mechanism for interconversion in the mouse intestine. In both in vitro and in vivo models, NOTCH suppression reduces the ratio of BMI1+/LGR5+ ISCs while NOTCH stimulation increases this ratio. Furthermore, NOTCH signaling can activate asymmetric division after intestinal inflammation. Overall, these data provide insights into ISC plasticity, demonstrating a direct interconversion mechanism between slow- and fast-cycling ISCs.

Authors
Srinivasan, T; Than, EB; Bu, P; Tung, K-L; Chen, K-Y; Augenlicht, L; Lipkin, SM; Shen, X
MLA Citation
Srinivasan, T, Than, EB, Bu, P, Tung, K-L, Chen, K-Y, Augenlicht, L, Lipkin, SM, and Shen, X. "Notch signalling regulates asymmetric division and inter-conversion between lgr5 and bmi1 expressing intestinal stem cells." Scientific reports 6 (May 16, 2016): 26069-.
PMID
27181744
Source
epmc
Published In
Scientific Reports
Volume
6
Publish Date
2016
Start Page
26069
DOI
10.1038/srep26069

A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division.

The roles of long non-coding RNAs (lncRNAs) in regulating cancer and stem cells are being increasingly appreciated. Its diverse mechanisms provide the regulatory network with a bigger repertoire to increase complexity. Here we report a novel LncRNA, Lnc34a, that is enriched in colon cancer stem cells (CCSCs) and initiates asymmetric division by directly targeting the microRNA miR-34a to cause its spatial imbalance. Lnc34a recruits Dnmt3a via PHB2 and HDAC1 to methylate and deacetylate the miR-34a promoter simultaneously, hence epigenetically silencing miR-34a expression independent of its upstream regulator, p53. Lnc34a levels affect CCSC self-renewal and colorectal cancer (CRC) growth in xenograft models. Lnc34a is upregulated in late-stage CRCs, contributing to epigenetic miR-34a silencing and CRC proliferation. The fact that lncRNA targets microRNA highlights the regulatory complexity of non-coding RNAs (ncRNAs), which occupy the bulk of the genome.

Authors
Wang, L; Bu, P; Ai, Y; Srinivasan, T; Chen, HJ; Xiang, K; Lipkin, SM; Shen, X
MLA Citation
Wang, L, Bu, P, Ai, Y, Srinivasan, T, Chen, HJ, Xiang, K, Lipkin, SM, and Shen, X. "A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division." eLife 5 (April 14, 2016).
Website
http://hdl.handle.net/10161/12053
PMID
27077950
Source
epmc
Published In
eLife
Volume
5
Publish Date
2016
DOI
10.7554/elife.14620

A real-time spike classification method based on dynamic time warping for extracellular enteric neural recording with large waveform variability.

Computationally efficient spike recognition methods are required for real-time analysis of extracellular neural recordings. The enteric nervous system (ENS) is important to human health but less well-understood with few appropriate spike recognition algorithms due to large waveform variability.Here we present a method based on dynamic time warping (DTW) with high tolerance to variability in time and magnitude. Adaptive temporal gridding for "fastDTW" in similarity calculation significantly reduces the computational cost. The automated threshold selection allows for real-time classification for extracellular recordings.Our method is first evaluated on synthesized data at different noise levels, improving both classification accuracy and computational complexity over the conventional cross-correlation based template-matching method (CCTM) and PCA+k-means clustering without time warping. Our method is then applied to analyze the mouse enteric neural recording with mechanical and chemical stimuli. Successful classification of biphasic and monophasic spikes is achieved even when the spike variability is larger than millisecond in width and millivolt in magnitude.In comparison with conventional template matching and clustering methods, the fastDTW method is computationally efficient with high tolerance to waveform variability.We have developed an adaptive fastDTW algorithm for real-time spike classification of ENS recording with large waveform variability against colony motility, ambient changes and cellular heterogeneity.

Authors
Cao, Y; Rakhilin, N; Gordon, PH; Shen, X; Kan, EC
MLA Citation
Cao, Y, Rakhilin, N, Gordon, PH, Shen, X, and Kan, EC. "A real-time spike classification method based on dynamic time warping for extracellular enteric neural recording with large waveform variability." Journal of neuroscience methods 261 (March 2016): 97-109.
PMID
26719239
Source
epmc
Published In
Journal of Neuroscience Methods
Volume
261
Publish Date
2016
Start Page
97
End Page
109
DOI
10.1016/j.jneumeth.2015.12.006

A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer.

Emerging evidence suggests that microRNAs can initiate asymmetric division, but whether microRNA and protein cell fate determinants coordinate with each other remains unclear. Here, we show that miR-34a directly suppresses Numb in early-stage colon cancer stem cells (CCSCs), forming an incoherent feedforward loop (IFFL) targeting Notch to separate stem and non-stem cell fates robustly. Perturbation of the IFFL leads to a new intermediate cell population with plastic and ambiguous identity. Lgr5+ mouse intestinal/colon stem cells (ISCs) predominantly undergo symmetric division but turn on asymmetric division to curb the number of ISCs when proinflammatory response causes excessive proliferation. Deletion of miR-34a inhibits asymmetric division and exacerbates Lgr5+ ISC proliferation under such stress. Collectively, our data indicate that microRNA and protein cell fate determinants coordinate to enhance robustness of cell fate decision, and they provide a safeguard mechanism against stem cell proliferation induced by inflammation or oncogenic mutation.

Authors
Bu, P; Wang, L; Chen, K-Y; Srinivasan, T; Murthy, PKL; Tung, K-L; Varanko, AK; Chen, HJ; Ai, Y; King, S; Lipkin, SM; Shen, X
MLA Citation
Bu, P, Wang, L, Chen, K-Y, Srinivasan, T, Murthy, PKL, Tung, K-L, Varanko, AK, Chen, HJ, Ai, Y, King, S, Lipkin, SM, and Shen, X. "A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer." Cell stem cell 18.2 (February 2016): 189-202.
Website
http://hdl.handle.net/10161/11645
PMID
26849305
Source
epmc
Published In
Cell Stem Cell
Volume
18
Issue
2
Publish Date
2016
Start Page
189
End Page
202
DOI
10.1016/j.stem.2016.01.006

Targeted drug delivery to circulating tumor cells via platelet membrane-functionalized particles.

Circulating tumor cells (CTCs) are responsible for metastases in distant organs via hematogenous dissemination. Fundamental studies in the past decade have suggested that neutralization of CTCs in circulation could represent an effective strategy to prevent metastasis. Current paradigms of targeted drug delivery into a solid tumor largely fall into two main categories: unique cancer markers (e.g. overexpression of surface receptors) and tumor-specific microenvironment (e.g. low pH, hypoxia, etc.). While relying on a surface receptor to target CTCs can be greatly challenged by cancer heterogeneity, targeting of tumor microenvironments has the advantage of recognizing a broader spectrum of cancer cells regardless of genetic differences or tumor types. The blood circulation, however, where CTCs transit through, lacks the same tumor microenvironment as that found in a solid tumor. In this study, a unique "microenvironment" was confirmed upon introduction of cancer cells of different types into circulation where activated platelets and fibrin were physically associated with blood-borne cancer cells. Inspired by this observation, synthetic silica particles were functionalized with activated platelet membrane along with surface conjugation of tumor-specific apoptosis-inducing ligand cytokine, TRAIL. Biomimetic synthetic particles incorporated into CTC-associated micro-thrombi in lung vasculature and dramatically decreased lung metastases in a mouse breast cancer metastasis model. Our results demonstrate a "Trojan Horse" strategy of neutralizing CTCs to attenuate metastasis.

Authors
Li, J; Ai, Y; Wang, L; Bu, P; Sharkey, CC; Wu, Q; Wun, B; Roy, S; Shen, X; King, MR
MLA Citation
Li, J, Ai, Y, Wang, L, Bu, P, Sharkey, CC, Wu, Q, Wun, B, Roy, S, Shen, X, and King, MR. "Targeted drug delivery to circulating tumor cells via platelet membrane-functionalized particles." Biomaterials 76 (January 2016): 52-65.
PMID
26519648
Source
epmc
Published In
Biomaterials
Volume
76
Publish Date
2016
Start Page
52
End Page
65
DOI
10.1016/j.biomaterials.2015.10.046

Surface Functionalized Graphene Biosensor on Sapphire for Cancer Cell Detection.

Graphene has several unique physical, optical and electrical properties such as a two-dimensional (2D) planar structure, high optical transparency and high carrier mobility at room temperature. These make graphene interesting for electrical biosensing. Using a catalyst-free chemical vapor deposition (CVD) method, graphene film is grown on a sapphire substrate. There is a single or a few sheets as confirmed by Raman spectroscopy and atomic force microscopy (AFM). Electrical graphene biosensors are fabricated to detect large-sized biological analytes such as cancer cells. Human colorectal carcinoma cells are sensed by the resistance change of an active bio-functionalized graphene device as the cells are captured by the immobilized antibody surface. The functionalized sensors show an increase in resistance as large as ~20% of the baseline with a small number of adhered cells. This study suggests that the bio-functionalized electrical graphene sensors on sapphire, which is a highly transparent material, can potentially detect circulating tumor cells (CTCs) and monitor cellular electrical behavior while being compatible with fluorescence-based optical-detection bioassays.

Authors
Joe, DJ; Hwang, J; Johnson, C; Cha, H-Y; Lee, J-W; Shen, X; Spencer, MG; Tiwari, S; Kim, M
MLA Citation
Joe, DJ, Hwang, J, Johnson, C, Cha, H-Y, Lee, J-W, Shen, X, Spencer, MG, Tiwari, S, and Kim, M. "Surface Functionalized Graphene Biosensor on Sapphire for Cancer Cell Detection." Journal of nanoscience and nanotechnology 16.1 (January 2016): 144-151.
PMID
27398439
Source
epmc
Published In
Journal of nanoscience and nanotechnology
Volume
16
Issue
1
Publish Date
2016
Start Page
144
End Page
151

IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation.

Endoplasmic reticulum (ER)-associated degradation (ERAD) represents a principle quality control mechanism to clear misfolded proteins in the ER; however, its physiological significance and the nature of endogenous ERAD substrates remain largely unexplored. Here we discover that IRE1α, the sensor of the unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. ERAD-mediated IRE1α degradation occurs under basal conditions in a BiP-dependent manner, requires both the intramembrane hydrophilic residues of IRE1α and the lectin protein OS9, and is attenuated by ER stress. ERAD deficiency causes IRE1α protein stabilization, accumulation and mild activation both in vitro and in vivo. Although enterocyte-specific Sel1L-knockout mice (Sel1L(ΔIEC)) are viable and seem normal, they are highly susceptible to experimental colitis and inflammation-associated dysbiosis, in an IRE1α-dependent but CHOP-independent manner. Hence, Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1α signalling in vivo by managing its protein turnover.

Authors
Sun, S; Shi, G; Sha, H; Ji, Y; Han, X; Shu, X; Ma, H; Inoue, T; Gao, B; Kim, H; Bu, P; Guber, RD; Shen, X; Lee, A-H; Iwawaki, T; Paton, AW; Paton, JC; Fang, D; Tsai, B; Yates, JR; Wu, H; Kersten, S; Long, Q; Duhamel, GE; Simpson, KW; Qi, L
MLA Citation
Sun, S, Shi, G, Sha, H, Ji, Y, Han, X, Shu, X, Ma, H, Inoue, T, Gao, B, Kim, H, Bu, P, Guber, RD, Shen, X, Lee, A-H, Iwawaki, T, Paton, AW, Paton, JC, Fang, D, Tsai, B, Yates, JR, Wu, H, Kersten, S, Long, Q, Duhamel, GE, Simpson, KW, and Qi, L. "IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation." Nature cell biology 17.12 (December 2015): 1546-1555.
PMID
26551274
Source
epmc
Published In
Nature Cell Biology
Volume
17
Issue
12
Publish Date
2015
Start Page
1546
End Page
1555
DOI
10.1038/ncb3266

Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.

Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening.

Authors
Chen, HJ; Sun, J; Huang, Z; Hou, H; Arcilla, M; Rakhilin, N; Joe, DJ; Choi, J; Gadamsetty, P; Milsom, J; Nandakumar, G; Longman, R; Zhou, XK; Edwards, R; Chen, J; Chen, KY; Bu, P; Wang, L; Xu, Y; Munroe, R; Abratte, C; Miller, AD; Gümüş, ZH; Shuler, M; Nishimura, N; Edelmann, W; Shen, X; Lipkin, SM
MLA Citation
Chen, HJ, Sun, J, Huang, Z, Hou, H, Arcilla, M, Rakhilin, N, Joe, DJ, Choi, J, Gadamsetty, P, Milsom, J, Nandakumar, G, Longman, R, Zhou, XK, Edwards, R, Chen, J, Chen, KY, Bu, P, Wang, L, Xu, Y, Munroe, R, Abratte, C, Miller, AD, Gümüş, ZH, Shuler, M, Nishimura, N, Edelmann, W, Shen, X, and Lipkin, SM. "Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting." Nature biotechnology 33.6 (June 2015): 656-660.
PMID
26006007
Source
epmc
Published In
Nature Biotechnology
Volume
33
Issue
6
Publish Date
2015
Start Page
656
End Page
660
DOI
10.1038/nbt.3239

miR-1269 promotes metastasis and forms a positive feedback loop with TGF-β.

As patient survival drops precipitously from early-stage cancers to late-stage and metastatic cancers, microRNAs that promote relapse and metastasis can serve as prognostic and predictive markers as well as therapeutic targets for chemoprevention. Here we show that miR-1269a promotes colorectal cancer (CRC) metastasis and forms a positive feedback loop with TGF-β signalling. miR-1269a is upregulated in late-stage CRCs, and long-term monitoring of 100 stage II CRC patients revealed that miR-1269a expression in their surgically removed primary tumours is strongly associated with risk of CRC relapse and metastasis. Consistent with clinical observations, miR-1269a significantly increases the ability of CRC cells to invade and metastasize in vivo. TGF-β activates miR-1269 via Sox4, while miR-1269a enhances TGF-β signalling by targeting Smad7 and HOXD10, hence forming a positive feedback loop. Our findings suggest that miR-1269a is a potential marker to inform adjuvant chemotherapy decisions for CRC patients and a potential therapeutic target to deter metastasis.

Authors
Bu, P; Wang, L; Chen, K-Y; Rakhilin, N; Sun, J; Closa, A; Tung, K-L; King, S; Kristine Varanko, A; Xu, Y; Huan Chen, J; Zessin, AS; Shealy, J; Cummings, B; Hsu, D; Lipkin, SM; Moreno, V; Gümüş, ZH; Shen, X
MLA Citation
Bu, P, Wang, L, Chen, K-Y, Rakhilin, N, Sun, J, Closa, A, Tung, K-L, King, S, Kristine Varanko, A, Xu, Y, Huan Chen, J, Zessin, AS, Shealy, J, Cummings, B, Hsu, D, Lipkin, SM, Moreno, V, Gümüş, ZH, and Shen, X. "miR-1269 promotes metastasis and forms a positive feedback loop with TGF-β." Nature communications 6 (April 15, 2015): 6879-.
PMID
25872451
Source
epmc
Published In
Nature Communications
Volume
6
Publish Date
2015
Start Page
6879
DOI
10.1038/ncomms7879

Epigenetics and cancer metabolism.

Cancer cells adapt their metabolism to support proliferation and survival. A hallmark of cancer, this alteration is characterized by dysfunctional metabolic enzymes, changes in nutrient availability, tumor microenvironment and oncogenic mutations. Metabolic rewiring in cancer is tightly connected to changes at the epigenetic level. Enzymes that mediate epigenetic status of cells catalyze posttranslational modifications of DNA and histones and influence metabolic gene expression. These enzymes require metabolites that are used as cofactors and substrates to carry out reactions. This interaction of epigenetics and metabolism constitutes a new avenue of cancer biology and could lead to new insights for the development of anti-cancer therapeutics.

Authors
Johnson, C; Warmoes, MO; Shen, X; Locasale, JW
MLA Citation
Johnson, C, Warmoes, MO, Shen, X, and Locasale, JW. "Epigenetics and cancer metabolism." Cancer letters 356.2 Pt A (January 2015): 309-314. (Review)
PMID
24125862
Source
epmc
Published In
Cancer Letters
Volume
356
Issue
2 Pt A
Publish Date
2015
Start Page
309
End Page
314
DOI
10.1016/j.canlet.2013.09.043

A Bio-inspired spatial patterning circuit

© 2014 IEEE.Lateral Inhibition (LI) is a widely conserved patterning mechanism in biological systems across species. Distinct from better-known Turing patterns, LI depend on cell-cell contact rather than diffusion. We built an in silico genetic circuit model to analyze the dynamic properties of LI. The model revealed that LI amplifies differences between neighboring cells to push them into opposite states, hence forming stable 2-D patterns. Inspired by this insight, we designed and implemented an electronic circuit that recapitulates LI patterning dynamics. This biomimetic system serve as a physical model to elucidate the design principle of generating robust patterning through spatial feedback, regardless of the underlying devices being biological or electrical.

Authors
Chen, KY; Joe, DJ; Shealy, JB; Land, BR; Shen, X
MLA Citation
Chen, KY, Joe, DJ, Shealy, JB, Land, BR, and Shen, X. "A Bio-inspired spatial patterning circuit." 2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBC 2014 (January 1, 2014): 86-89.
Source
scopus
Published In
2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBC 2014
Publish Date
2014
Start Page
86
End Page
89
DOI
10.1109/EMBC.2014.6943535

Nonamperometric CMOS sensing of intestinal action potentials

© 14CBMS.A CMOS floating-gate, non-amperometric electrochemical sensor, which overcomes the invasiveness of patch-clamp and bias-setting of Ion Sensitive FET (ISFET), is proposed to detect enteric nerve system (ENS) action potentials (AP) by model-based match filtering. With the cellular HodgkinHuxley (HH) models of S-type and AH-type neurons, we robustly capture AP from freshly harvested mouse intestinal tissues.

Authors
Cao, Y; Rakhilin, N; Shen, X; Kan, EC
MLA Citation
Cao, Y, Rakhilin, N, Shen, X, and Kan, EC. "Nonamperometric CMOS sensing of intestinal action potentials." 18th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2014 (January 1, 2014): 2064-2066.
Source
scopus
Published In
18th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2014
Publish Date
2014
Start Page
2064
End Page
2066

A metabolic signature of colon cancer initiating cells.

Colon cancer initiating cells (CCICs) are more tumorigenic and metastatic than the majority of colorectal cancer (CRC) cells. CCICs have also been associated with stem cell-like properties. However, there is a lack of system-level understanding of what mechanisms distinguish CCICs from common CRC cells. We compared the transcriptomes of CD133+ CCICs and CD133- CRC cells from multiple sources, which identified a distinct metabolic signature for CD133(high) CCICs. High-resolution unbiased metabolomics was then performed to validate this CCIC metabolic signature. Specifically, levels of enzymes and metabolites involved in glycolysis, the citric acid (TCA) cycle, and cysteine and methionine metabolism are altered in CCICs. Analyses of the alterations further suggest an epigenetic link. This metabolic signature provides mechanistic insights into CCIC phenotypes and may serve as potential biomarkers and therapeutic targets for future CRC treatment.

Authors
Chen, K-Y; Liu, X; Bu, P; Lin, C-S; Rakhilin, N; Locasale, JW; Shen, X
MLA Citation
Chen, K-Y, Liu, X, Bu, P, Lin, C-S, Rakhilin, N, Locasale, JW, and Shen, X. "A metabolic signature of colon cancer initiating cells." Conference proceedings : .. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference 2014 (January 2014): 4759-4762.
PMID
25571056
Source
epmc
Published In
Annual International Conference of the IEEE Engineering in Medicine and Biology - Proceedings
Volume
2014
Publish Date
2014
Start Page
4759
End Page
4762
DOI
10.1109/embc.2014.6944688

Post-translational regulation enables robust p53 regulation.

The tumor suppressor protein p53 plays important roles in DNA damage repair, cell cycle arrest and apoptosis. Due to its critical functions, the level of p53 is tightly regulated by a negative feedback mechanism to increase its tolerance towards fluctuations and disturbances. Interestingly, the p53 level is controlled by post-translational regulation rather than transcriptional regulation in this feedback mechanism.We analyzed the dynamics of this feedback to understand whether post-translational regulation provides any advantages over transcriptional regulation in regard to disturbance rejection. When a disturbance happens, even though negative feedback reduces the steady-state error, it can cause a system to become less stable and transiently overshoots, which may erroneously trigger downstream reactions. Therefore, the system needs to balance the trade-off between steady-state and transient errors. Feedback control and adaptive estimation theories revealed that post-translational regulation achieves a better trade-off than transcriptional regulation, contributing to a more steady level of p53 under the influence of noise and disturbances. Furthermore, post-translational regulation enables cells to respond more promptly to stress conditions with consistent amplitude. However, for better disturbance rejection, the p53- Mdm2 negative feedback has to pay a price of higher stochastic noise.Our analyses suggest that the p53-Mdm2 feedback favors regulatory mechanisms that provide the optimal trade-offs for dynamic control.

Authors
Shin, Y-J; Chen, K-Y; Sayed, AH; Hencey, B; Shen, X
MLA Citation
Shin, Y-J, Chen, K-Y, Sayed, AH, Hencey, B, and Shen, X. "Post-translational regulation enables robust p53 regulation." BMC systems biology 7 (August 30, 2013): 83-.
PMID
23992617
Source
epmc
Published In
BMC Systems Biology
Volume
7
Publish Date
2013
Start Page
83
DOI
10.1186/1752-0509-7-83

Asymmetric division: a marker for cancer stem cells in early stage tumors?

Authors
Bu, P; Chen, K-Y; Lipkin, SM; Shen, X
MLA Citation
Bu, P, Chen, K-Y, Lipkin, SM, and Shen, X. "Asymmetric division: a marker for cancer stem cells in early stage tumors?." Oncotarget 4.7 (July 2013): 950-951.
PMID
23807730
Source
epmc
Published In
Oncotarget
Volume
4
Issue
7
Publish Date
2013
Start Page
950
End Page
951

A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells.

microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.

Authors
Bu, P; Chen, K-Y; Chen, JH; Wang, L; Walters, J; Shin, YJ; Goerger, JP; Sun, J; Witherspoon, M; Rakhilin, N; Li, J; Yang, H; Milsom, J; Lee, S; Zipfel, W; Jin, MM; Gümüş, ZH; Lipkin, SM; Shen, X
MLA Citation
Bu, P, Chen, K-Y, Chen, JH, Wang, L, Walters, J, Shin, YJ, Goerger, JP, Sun, J, Witherspoon, M, Rakhilin, N, Li, J, Yang, H, Milsom, J, Lee, S, Zipfel, W, Jin, MM, Gümüş, ZH, Lipkin, SM, and Shen, X. "A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells." Cell stem cell 12.5 (May 2013): 602-615.
PMID
23642368
Source
epmc
Published In
Cell Stem Cell
Volume
12
Issue
5
Publish Date
2013
Start Page
602
End Page
615
DOI
10.1016/j.stem.2013.03.002

Spatial perturbation with synthetic protein scaffold reveals robustness of asymmetric cell division.

Asymmetric cell division is an important mechanism for creating diversity in a cellular population. Stem cells commonly perform asymmetric division to generate both a daughter stem cell for self-renewal and a more differentiated daughter cell to populate the tissue. During asymmetric cell division, protein cell fate determinants asymmetrically localize to the opposite poles of a dividing cell to cause distinct cell fate. However, it remains unclear whether cell fate determination is robust to fluctuations and noise during this spatial allocation process. To answer this question, we engineered Caulobacter, a bacterial model for asymmetric division, to express synthetic scaffolds with modular protein interaction domains. These scaffolds perturbed the spatial distribution of the PleC-DivJ-DivK phospho-signaling network without changing their endogenous expression levels. Surprisingly, enforcing symmetrical distribution of these cell fate determinants did not result in symmetric daughter fate or any morphological defects. Further computational analysis suggested that PleC and DivJ form a robust phospho-switch that can tolerate high amount of spatial variation. This insight may shed light on the presence of similar phospho-switches in stem cell asymmetric division regulation. Overall, our study demonstrates that synthetic protein scaffolds can provide a useful tool to probe biological systems for better understanding of their operating principles.

Authors
Li, J; Bu, P; Chen, K-Y; Shen, X
MLA Citation
Li, J, Bu, P, Chen, K-Y, and Shen, X. "Spatial perturbation with synthetic protein scaffold reveals robustness of asymmetric cell division." Journal of biomedical science and engineering 6.2 (February 2013): 134-143.
PMID
25750689
Source
epmc
Published In
Journal of Biomedical Science and Engineering
Volume
6
Issue
2
Publish Date
2013
Start Page
134
End Page
143

Chemokine 25-induced signaling suppresses colon cancer invasion and metastasis.

Chemotactic cytokines (chemokines) can help regulate tumor cell invasion and metastasis. Here, we show that chemokine 25 (CCL25) and its cognate receptor chemokine receptor 9 (CCR9) inhibit colorectal cancer (CRC) invasion and metastasis. We found that CCR9 protein expression levels were highest in colon adenomas and progressively decreased in invasive and metastatic CRCs. CCR9 was expressed in both primary tumor cell cultures and colon-cancer-initiating cell (CCIC) lines derived from early-stage CRCs but not from metastatic CRC. CCL25 stimulated cell proliferation by activating AKT signaling. In vivo, systemically injected CCR9+ early-stage CCICs led to the formation of orthotopic gastrointestinal xenograft tumors. Blocking CCR9 signaling inhibited CRC tumor formation in the native gastrointestinal CCL25+ microenvironment, while increasing extraintestinal tumor incidence. NOTCH signaling, which promotes CRC metastasis, increased extraintestinal tumor frequency by stimulating CCR9 proteasomal degradation. Overall, these data indicate that CCL25 and CCR9 regulate CRC progression and invasion and further demonstrate an appropriate in vivo experimental system to study CRC progression in the native colon microenvironment.

Authors
Chen, HJ; Edwards, R; Tucci, S; Bu, P; Milsom, J; Lee, S; Edelmann, W; Gümüs, ZH; Shen, X; Lipkin, S
MLA Citation
Chen, HJ, Edwards, R, Tucci, S, Bu, P, Milsom, J, Lee, S, Edelmann, W, Gümüs, ZH, Shen, X, and Lipkin, S. "Chemokine 25-induced signaling suppresses colon cancer invasion and metastasis." The Journal of clinical investigation 122.9 (September 2012): 3184-3196.
PMID
22863617
Source
epmc
Published In
Journal of Clinical Investigation
Volume
122
Issue
9
Publish Date
2012
Start Page
3184
End Page
3196
DOI
10.1172/jci62110

Using an adaptive gene network model for self-organizing multicellular behavior.

Using the transient interleukin (IL)-2 secretion of effector T helper (T(eff)) cells as an example, we show that self-organizing multicellular behavior can be modeled and predicted by an adaptive gene network model. Incorporating an adaptation algorithm we established previously, we construct a network model that has the parameter values iteratively updated to cope with environmental change governed by diffusion and cell-cell interactions. In contrast to non-adaptive models, we find that the proposed adaptive model for individual T(eff) cells can generate transient IL-2 secretory behavior that is observed experimentally at the population level. The proposed adaptive modeling approach can be a useful tool in the study of self-organizing behavior observed in other contexts in biology, including microbial pathogenesis, antibiotic resistance, embryonic development, tumor formation, etc.

Authors
Shin, Y-J; Sayed, AH; Shen, X
MLA Citation
Shin, Y-J, Sayed, AH, and Shen, X. "Using an adaptive gene network model for self-organizing multicellular behavior." Conference proceedings : .. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference 2012 (January 2012): 5449-5453.
PMID
23367162
Source
epmc
Published In
Annual International Conference of the IEEE Engineering in Medicine and Biology - Proceedings
Volume
2012
Publish Date
2012
Start Page
5449
End Page
5453
DOI
10.1109/embc.2012.6347227

Adaptive models for gene networks.

Biological systems are often treated as time-invariant by computational models that use fixed parameter values. In this study, we demonstrate that the behavior of the p53-MDM2 gene network in individual cells can be tracked using adaptive filtering algorithms and the resulting time-variant models can approximate experimental measurements more accurately than time-invariant models. Adaptive models with time-variant parameters can help reduce modeling complexity and can more realistically represent biological systems.

Authors
Shin, Y-J; Sayed, AH; Shen, X
MLA Citation
Shin, Y-J, Sayed, AH, and Shen, X. "Adaptive models for gene networks." PloS one 7.2 (January 2012): e31657-.
PMID
22359614
Source
epmc
Published In
PloS one
Volume
7
Issue
2
Publish Date
2012
Start Page
e31657
DOI
10.1371/journal.pone.0031657

Using an adaptive gene network model for self-organizing multicellular behavior.

Using the transient interleukin (IL)-2 secretion of effector T helper (T(eff)) cells as an example, we show that self-organizing multicellular behavior can be modeled and predicted by an adaptive gene network model. Incorporating an adaptation algorithm we established previously, we construct a network model that has the parameter values iteratively updated to cope with environmental change governed by diffusion and cell-cell interactions. In contrast to non-adaptive models, we find that the proposed adaptive model for individual T(eff) cells can generate transient IL-2 secretory behavior that is observed experimentally at the population level. The proposed adaptive modeling approach can be a useful tool in the study of self-organizing behavior observed in other contexts in biology, including microbial pathogenesis, antibiotic resistance, embryonic development, tumor formation, etc.

Authors
Shin, Y-J; Sayed, AH; Shen, X
MLA Citation
Shin, Y-J, Sayed, AH, and Shen, X. "Using an adaptive gene network model for self-organizing multicellular behavior." Conference proceedings : .. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference (2012): 5449-5453.
Source
scival
Published In
Annual International Conference of the IEEE Engineering in Medicine and Biology - Proceedings
Publish Date
2012
Start Page
5449
End Page
5453
DOI
10.1109/EMBC.2012.6347227

Disturbance rejection helps modulate the P53 oscillation

Designing a system that adequately processes the input and that rejects the effects of disturbance is a central theme in feedback control theory. In this paper, we use the concept of "disturbance rejection" to analyze the oscillatory behavior of p53, a well-known tumor suppressor protein. Our analysis reveals that the p53 oscillation is not completely dictated by the p53-MDM2 negative feedback loopit is also modulated by periodic DNA repair-related fluctuations. According to our disturbance rejection model, the feedback loop normally filters the effects of noise and fluctuations on p53, but upon DNA damage, it stops performing the filtering function so that DNA repair-related fluctuations can modulate the p53 oscillation. Our analysis suggests that the overexpression of MDM2, observed in many types of cancer, can make the feedback mechanism less responsive to the modulating signals after DNA damage occurs. Copyright © 2011 by ASME.

Authors
Shin, YJ; Lipkin, SM; Hencey, B; Shen, X
MLA Citation
Shin, YJ, Lipkin, SM, Hencey, B, and Shen, X. "Disturbance rejection helps modulate the P53 oscillation." ASME 2011 Dynamic Systems and Control Conference and Bath/ASME Symposium on Fluid Power and Motion Control, DSCC 2011 2 (December 1, 2011): 557-563.
Source
scopus
Published In
ASME 2011 Dynamic Systems and Control Conference and Bath/ASME Symposium on Fluid Power and Motion Control, DSCC 2011
Volume
2
Publish Date
2011
Start Page
557
End Page
563
DOI
10.1115/DSCC2011-6046

Joint DAC/IWBDA special session design and synthesis of biological circuits

With the growing complexity of synthetic biological circuits, robust and systematic methods are needed for design and test. Leveraging lessons learned from the semiconductor and design automation industries, synthetic biologists are starting to adopt computer-aided design and verification software with some success. However, due to the great challenges associated with designing synthetic biological circuits, this nascent approach has to address many problems not present in electronic circuits. In this session, three leading synthetic biologists will share how they have developed software tools to help design and verify their synthetic circuits, the unique challenges they face, and their insights into the next generation of tools for synthetic biology. © 2011 ACM.

Authors
Densmore, D; Horowitz, M; Krishnaswamy, S; Shen, X; Arkin, A; Winfree, E; Voigt, C
MLA Citation
Densmore, D, Horowitz, M, Krishnaswamy, S, Shen, X, Arkin, A, Winfree, E, and Voigt, C. "Joint DAC/IWBDA special session design and synthesis of biological circuits." Proceedings - Design Automation Conference (September 16, 2011): 114-115.
Source
scopus
Published In
Design Automation Conference
Publish Date
2011
Start Page
114
End Page
115

Frequency domain analysis reveals external periodic fluctuations can generate sustained p53 oscillation.

p53 is a well-known tumor suppressor protein that regulates many pathways, such as ones involved in cell cycle and apoptosis. The p53 levels are known to oscillate without damping after DNA damage, which has been a focus of many recent studies. A negative feedback loop involving p53 and MDM2 has been reported to be responsible for this oscillatory behavior, but questions remain as how the dynamics of this loop alter in order to initiate and maintain the sustained or undamped p53 oscillation. Our frequency domain analysis suggests that the sustained p53 oscillation is not completely dictated by the negative feedback loop; instead, it is likely to be also modulated by periodic DNA repair-related fluctuations that are triggered by DNA damage. According to our analysis, the p53-MDM2 feedback mechanism exhibits adaptability in different cellular contexts. It normally filters noise and fluctuations exerted on p53, but upon DNA damage, it stops performing the filtering function so that DNA repair-related oscillatory signals can modulate the p53 oscillation. Furthermore, it is shown that the p53-MDM2 feedback loop increases its damping ratio allowing p53 to oscillate at a frequency more synchronized with the other cellular efforts to repair the damaged DNA, while suppressing its inherent oscillation-generating capability. Our analysis suggests that the overexpression of MDM2, observed in many types of cancer, can disrupt the operation of this adaptive mechanism by making it less responsive to the modulating signals after DNA damage occurs.

Authors
Shin, Y-J; Hencey, B; Lipkin, SM; Shen, X
MLA Citation
Shin, Y-J, Hencey, B, Lipkin, SM, and Shen, X. "Frequency domain analysis reveals external periodic fluctuations can generate sustained p53 oscillation." PloS one 6.7 (January 2011): e22852-.
PMID
21829536
Source
epmc
Published In
PloS one
Volume
6
Issue
7
Publish Date
2011
Start Page
e22852
DOI
10.1371/journal.pone.0022852

An essential transcription factor, SciP, enhances robustness of Caulobacter cell cycle regulation.

A cyclical control circuit composed of four master regulators drives the Caulobacter cell cycle. We report that SciP, a helix-turn-helix transcription factor, is an essential component of this circuit. SciP is cell cycle-controlled and co-conserved with the global cell cycle regulator CtrA in the α-proteobacteria. SciP is expressed late in the cell cycle and accumulates preferentially in the daughter swarmer cell. At least 58 genes, including many flagellar and chemotaxis genes, are regulated by a type 1 incoherent feedforward motif in which CtrA activates sciP, followed by SciP repression of ctrA and CtrA target genes. We demonstrate that SciP binds to DNA at a motif distinct from the CtrA binding motif that is present in the promoters of genes co-regulated by SciP and CtrA. SciP overexpression disrupts the balance between activation and repression of the CtrA-SciP coregulated genes yielding filamentous cells and loss of viability. The type 1 incoherent feedforward circuit motif enhances the pulse-like expression of the downstream genes, and the negative feedback to ctrA expression reduces peak CtrA accumulation. The presence of SciP in the control network enhances the robustness of the cell cycle to varying growth rates.

Authors
Tan, MH; Kozdon, JB; Shen, X; Shapiro, L; McAdams, HH
MLA Citation
Tan, MH, Kozdon, JB, Shen, X, Shapiro, L, and McAdams, HH. "An essential transcription factor, SciP, enhances robustness of Caulobacter cell cycle regulation." Proceedings of the National Academy of Sciences of the United States of America 107.44 (November 2010): 18985-18990.
PMID
20956288
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
107
Issue
44
Publish Date
2010
Start Page
18985
End Page
18990
DOI
10.1073/pnas.1014395107

The class I HDAC inhibitor MGCD0103 induces cell cycle arrest and apoptosis in colon cancer initiating cells by upregulating Dickkopf-1 and non-canonical Wnt signaling.

Colorectal cancer metastatic recurrence and chemoresistance are major causes of morbidity and mortality. Colon cancer initiating cells (CCIC) are thought to contribute to both these processes. To identify drugs with anti-CCIC activity we screened a number of FDA approved and investigational compounds. We found that the class I selective histone deacetylase inhibitor (HDACi) MGCD0103 has significant activity against CCIC, and also significantly inhibits non-CCIC CRC cell xenograft formation. Both MGCD0103 and the pan-HDAC inhibitor Trichostatin impairs CCIC clonogenicity and cause cell cycle arrest and cell death. Gene expression profiling revealed that the canonical WNT ligand DKK-1 is a highly upregulated target of HDAC inhibitors. Despite the presence of APC mutations and constitutive WNT signaling in CCIC, both transfected and recombinant DKK-1 dramatically inhibit CCIC proliferation and clonogenicity. Overall, these data show that inhibition of class I HDACs is a promising novel approach to target both CCIC and non-CCIC CRC cells. Our studies also provide novel insights into roles for DKK1 in addition to canonical WNT signaling and the mechanism of CCIC tumor formation.

Authors
Sikandar, S; Dizon, D; Shen, X; Li, Z; Besterman, J; Lipkin, SM
MLA Citation
Sikandar, S, Dizon, D, Shen, X, Li, Z, Besterman, J, and Lipkin, SM. "The class I HDAC inhibitor MGCD0103 induces cell cycle arrest and apoptosis in colon cancer initiating cells by upregulating Dickkopf-1 and non-canonical Wnt signaling." Oncotarget 1.7 (November 2010): 596-605.
PMID
21317455
Source
epmc
Published In
Oncotarget
Volume
1
Issue
7
Publish Date
2010
Start Page
596
End Page
605

Architecture and inherent robustness of a bacterial cell-cycle control system.

A closed-loop control system drives progression of the coupled stalked and swarmer cell cycles of the bacterium Caulobacter crescentus in a near-mechanical step-like fashion. The cell-cycle control has a cyclical genetic circuit composed of four regulatory proteins with tight coupling to processive chromosome replication and cell division subsystems. We report a hybrid simulation of the coupled cell-cycle control system, including asymmetric cell division and responses to external starvation signals, that replicates mRNA and protein concentration patterns and is consistent with observed mutant phenotypes. An asynchronous sequential digital circuit model equivalent to the validated simulation model was created. Formal model-checking analysis of the digital circuit showed that the cell-cycle control is robust to intrinsic stochastic variations in reaction rates and nutrient supply, and that it reliably stops and restarts to accommodate nutrient starvation. Model checking also showed that mechanisms involving methylation-state changes in regulatory promoter regions during DNA replication increase the robustness of the cell-cycle control. The hybrid cell-cycle simulation implementation is inherently extensible and provides a promising approach for development of whole-cell behavioral models that can replicate the observed functionality of the cell and its responses to changing environmental conditions.

Authors
Shen, X; Collier, J; Dill, D; Shapiro, L; Horowitz, M; McAdams, HH
MLA Citation
Shen, X, Collier, J, Dill, D, Shapiro, L, Horowitz, M, and McAdams, HH. "Architecture and inherent robustness of a bacterial cell-cycle control system." Proceedings of the National Academy of Sciences of the United States of America 105.32 (August 6, 2008): 11340-11345.
PMID
18685108
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
105
Issue
32
Publish Date
2008
Start Page
11340
End Page
11345
DOI
10.1073/pnas.0805258105

Compensation for multimode fiber dispersion by adaptive optics.

Adaptive optics is used to compensate for modal dispersion in digital transmission through multimode fiber (MMF). At the transmitter, a spatial light modulator (SLM) controls the launched field pattern. An estimate of intersymbol interference (ISI) caused by modal dispersion is formed at the receiver and fed back to the transmitter, where the SLM is adjusted to minimize ISI. Error-free transmission of 10 Gbit/s non-return-to-zero signals through standard 50 microm graded-index MMFs up to 11.1 km long is demonstrated. It is shown that a single SLM can compensate for modal dispersion across a 600 GHz bandwidth.

Authors
Shen, X; Kahn, JM; Horowitz, MA
MLA Citation
Shen, X, Kahn, JM, and Horowitz, MA. "Compensation for multimode fiber dispersion by adaptive optics." Optics letters 30.22 (November 2005): 2985-2987.
PMID
16315696
Source
epmc
Published In
Optics Letters
Volume
30
Issue
22
Publish Date
2005
Start Page
2985
End Page
2987
DOI
10.1364/ol.30.002985

Compensation of multimode fiber dispersion using adaptive optics

Adaptive optics (AO) is used to compensate modal dispersion in multimode fiber. Transmission of 10 Gb/s NRZ data through standard 50-μm fibers up to 11.1 km long is demonstrated.

Authors
Shen, X; Kahn, JM; Horowitz, MA
MLA Citation
Shen, X, Kahn, JM, and Horowitz, MA. "Compensation of multimode fiber dispersion using adaptive optics." January 1, 2005.
Source
scopus
Published In
IET Conference Publications
Volume
2005
Issue
CP502
Publish Date
2005
Start Page
327
End Page
328
DOI
10.1049/cp:20050501
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