Jen-Tsan Chi
Professor in Molecular Genetics and Mirobiology
Overview
We are using functional genomic approaches to investigate the nutrient signaling and stress adaptations of cancer cells when exposed to various nutrient deprivations and microenvironmental stress conditions. Recently, we focus on two areas. First, we are elucidating the genetic determinants and disease relevance of ferroptosis, a newly recognized form of cell death. Second, we have identified the mammalian stringent response pathway which is highly similar to bacterial stringent response, but with some very interesting twists and novel mechanisms.
A. The genetic determinants and disease relevance of ferroptosis
Ferroptosis is a newly recognized form of cell death that is characterized by iron dependency and lipid peroxidation. The importance of ferroptosis is being recognized in many human diseases, including cancers, ischemia injuries, and neurodegeneration. Previously, we have identified the profound cystine addiction of renal cell carcinoma (1), breast cancer cells (2, 3), and ovarian cancer cells (4). Based on the concept that cystine deprivation triggers the ferroptosis due to the unopposed oxidative stresses, we have performed functional genomic screens to identify many novel genetic determinants of ferroptosis. For example, we have found that DNA damage response and ATM kinase regulate ferroptosis via affecting iron metabolism (5). This finding supports the potential of ionizing radiation to trigger DNA damage response and synergize with ferroptosis to treat human cancers. In addition, we found that ferroptosis is highly regulated by cell density. When cells are grown at low density, they are highly susceptible to ferroptosis. In contrast, the same cells become resistant to ferroptosis when grown at high density and confluency. we have found the Hippo pathway effectors TAZ and YAP are responsible for the cell density-dependent ferroptosis (4, 6, 7). Right now, we are pursuing several other novel determinants of ferroptosis that will reveal surprising insights into this new form of cell death.
B. A new stress pathway – mammalian stress response
All living organisms encounter a wide variety of nutrient deprivations and environmental stresses. Therefore, all organisms have developed various mechanisms to respond and promote survival under stress. In bacteria, the main strategy is “stringent response” triggered by the accumulation of the alarmone (p)ppGpp (shortened to ppGpp below) via regulation of its synthetase RelA and its hydrolase SpoT (8). The ppGpp binds to the transcription factor DksA and RNA polymerase to orchestrate extensive transcriptional changes that repress proliferation and promote stress survival (8, 9). While highly conserved among bacteria, the stringent response had not been reported in metazoans. However, a recent study identified Drosophila and human MESH1 (Metazoan SpoT Homolog 1) as the homologs of the ppGpp hydrolase domain of the bacterial SpoT (10). Both MESH1 proteins exhibit ppGpp hydrolase activity, and the deletion of Mesh1 in Drosophila led to a transcriptional response reminiscent of the bacterial stringent response (10). Recently, we have found that the genetic removal of MESH1 in tumor cells triggers extensive transcriptional changes and confers protection against oxidative stress-induced ferroptosis (11). Importantly, MESH1 removal also triggers proliferative arrest and other robust anti-tumor effects. Therefore, MESH1 knockdown leads to both stress survival and proliferation arrest, two cardinal features highly reminiscent of the bacterial stringent response. Therefore, we termed this pathway as “mammalian stringent response” (12). We have found that NADPH is the relevant MESH1 in the contexts of ferroptosis (13). Now, we are investigating how MESH1 removal leads to proliferation of arrests and anti-tumor phenotypes. Furthermore, we have found several other substrates of MESH1. We are investigating their function using culture cells, MESH1 KO mice, and other model organisms.
C. Genomic and single cell RNA analysis of Red Blood Cells
Red blood cells (RBC) are responsible for oxygen delivery to muscles during vigorous exercise. Therefore, many doping efforts focus on increasing RBC number and function to boost athletic performance during competition. For many decades, RBC were thought to be merely identical “sacs of hemoglobin” with no discernable differences due to factors such as age or pre-transfusion storage time. Additionally, because RBC lose their nuclei during terminal differentiation, they were not believed to retain any genetic materials. These long-held beliefs have now been disproven and the results have significant implications for detecting autologous blood transfusion (ABT) doping in athletes. We were among the first to discover that RBCs contain abundant and diverse species of RNAs. Using this knowledge, we subsequently optimized protocols and performed genomic analysis of the RBC transcriptome in sickle cell disease; these results revealed that heterogeneous RBCs could be divided into several subpopulations, which had implications for the mechanisms of malaria resistance. As an extension of these studies, we used high resolution Illumina RNA-Seq approaches to identify hundreds of additional known and novel microRNAs, mRNAs, and other RNA species in RBCs. This dynamic RBC transcriptome represents a significant opportunity to assess the impact that environmental factors (such as pre-transfusion refrigerate storage) on the RBC transcriptome. We have now identified a >10-fold change in miR-720 as well as several other RNA transcripts whose levels are significantly altered by RBC storage (14) which gained significant press coverage. We are pursuing the genomic and single cell analysis of RNA transcriptome in the context of blood doping, sickle cell diseases and other red cell diseases.
1. Tang X, Wu J, Ding CK, Lu M, Keenan MM, Lin CC, et al. Cystine Deprivation Triggers Programmed Necrosis in VHL-Deficient Renal Cell Carcinomas. Cancer Res. 2016;76(7):1892-903.
2. Tang X, Ding CK, Wu J, Sjol J, Wardell S, Spasojevic I, et al. Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling. Oncogene. 2017;36(30):4379.
3. Lin CC, Mabe NW, Lin YT, Yang WH, Tang X, Hong L, et al. RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence. Cell Death Differ. 2020.
4. Yang WH, Huang Z, Wu J, Ding C-KC, Murphy SK, Chi J-T. A TAZ-ANGPTL4-NOX2 axis regulates ferroptotic cell death and chemoresistance in epithelial ovarian cancer. Molecular Cancer Research. 2019: molcanres.0691.2019.
5. Chen PH, Wu J, Ding CC, Lin CC, Pan S, Bossa N, et al. Kinome screen of ferroptosis reveals a novel role of ATM in regulating iron metabolism. Cell Death Differ. 2019.
6. Yang W-H, Chi J-T. Hippo pathway effectors YAP/TAZ as novel determinants of ferroptosis. Molecular & Cellular Oncology. 2019:1699375.
7. Yang WH, Ding CKC, Sun T, Hsu DS, Chi JT. The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma Cell Reports. 2019;28(10):2501-8.e4.
8. Potrykus K, Cashel M. (p)ppGpp: still magical? Annu Rev Microbiol. 2008;62:35-51.
9. Kriel A, Bittner AN, Kim SH, Liu K, Tehranchi AK, Zou WY, et al. Direct regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance. Mol Cell. 2012;48(2):231-41.
10. Sun D, Lee G, Lee JH, Kim HY, Rhee HW, Park SY, et al. A metazoan ortholog of SpoT hydrolyzes ppGpp and functions in starvation responses. Nat Struct Mol Biol. 2010;17(10):1188-94.
11. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060-72.
12. Ding C-KC, Rose J, Wu J, Sun T, Chen K-Y, Chen P-H, et al. Mammalian stringent-like response mediated by the cytosolic NADPH phosphatase MESH1. bioRxiv. 2018.
13. Ding C-KC, Rose J, Sun T, Wu J, Chen P-H, Lin C-C, et al. MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nature Metabolism. 2020.
14. Yang WH, Doss JF, Walzer KA, McNulty SM, Wu J, Roback JD, et al. Angiogenin-mediated tRNA cleavage as a novel feature of stored red blood cells. Br J Haematol. 2018.
Positions
Professor in Molecular Genetics and Mirobiology in the School of Medicine
2023 School of Medicine
Assistant Professor of Medicine in the School of Medicine
2005 School of Medicine
Professor of Cell Biology in the School of Medicine
2023 School of Medicine
Professor of Pharmacology and Cancer Biology in the School of Medicine
2023 School of Medicine
Associate Professor of Cell Biology in the School of Medicine
2023 School of Medicine
Member of the Duke Cancer Institute in the School of Medicine
2004 School of Medicine
Education
M.D. 1991
1991 National Taiwan University (Taiwan)
Ph.D. 2000
2000 Stanford University
Postdoctoral Research, Biochemistry
2004 Stanford University
Publications, Grants & Awards
- Grants (54)
- Awards (3)
- Academics Articles (155)
- Conference Pages (28)
- Book Sections (2)
National Institutes of Health
National Institutes of Health
National Institutes of Health
Department of Defense
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
Department of Defense
University of North Carolina - Chapel Hill
Ovarian Cancer Research Alliance
National Institutes of Health
American Association for the Study of Liver Diseases
National Institutes of Health
Department of Defense
Department of Defense
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
Department of Defense
National Institutes of Health
Partnership for Clean Competition
National Institutes of Health
National Institutes of Health
Partnership for Clean Competition
V Foundation for Cancer Research
National Institutes of Health
National Institutes of Health
Partnership for Clean Competition
St. Baldrick's Foundation
Partnership for Clean Competition
National Institutes of Health
National Institutes of Health
National Institutes of Health
Department of Defense
Department of Defense
National Institutes of Health
National Institutes of Health
Department of Defense
World Anti-Doping Agency
New York Blood Center
Department of Defense
National Cancer Institute
National Institutes of Health
National Institutes of Health
World Anti-Doping Agency
National Institutes of Health
M2 Photonics Innovations
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
American Society of Clinical Investigation
Burroughs Wellcome Fund
Nature Communications
Data in Brief
Prostate Cancer Prostatic Dis
Cell Death & Disease
Molecular Therapy : the Journal of the American Society of Gene Therapy
Frontiers in Physiology
Computational and Structural Biotechnology Journal
Cells
Cell Death & Disease
Nature Communications
Genes and Diseases
Cell Death & Disease
J Tissue Eng
Frontiers in Cell and Developmental Biology
Cell Reports
Oncotarget
Biology
Cell Death Differ
Cell Death Differ
Nature Metabolism
Mol Cancer Res
Molecular & Cellular Oncology
Microsystems and Nanoengineering
Arthritis Research & Therapy
Journal of Translational Medicine
Oncogene
Oncogene
Current Pathobiology Reports
Molecular & Cellular Oncology
J Immunol Methods
J Proteome Res
Blood
Blood
Scientific Reports
Plos One
Journal of Visualized Experiments : Jove
Bmc Genomics
Clinical Cancer Research
Journal of Medicinal Chemistry
Plos Genet
Nature Communications
Int J Radiat Oncol Biol Phys
Cell Reports
Thromb Res
Mol Cancer Ther
Cancer J
Breast Cancer Res
Molecular Biology of the Cell
Breast Cancer Res
J Clin Invest
Cancer & Metabolism
Prostate Cancer and Prostatic Diseases
Prostate Cancer Prostatic Dis
Prostate Cancer Prostatic Dis
J Am Coll Cardiol
Semin Radiat Oncol
Molecular Cancer Therapeutics
Plos One
Circulation
Proc Natl Acad Sci U S A
Cell Host Microbe
Journal of Thrombosis and Thrombolysis
Journal of Cancer Epidemiology
Cancer Research
International Journal of Radiation Oncology, Biology, Physics
Mol Biochem Parasitol
Sci Transl Med
Breast Cancer Res
Clinical Cancer Research
Plos Genet
Plos Computational Biology
Clin Exp Optom
Cancer Cell
The Annals of Applied Statistics
Plos Computational Biology
Antioxidants & Redox Signaling
Journal of Rnai and Gene Silencing : an International Journal of Rna and Gene Targeting Research
Plos Medicine
Breast Cancer Res
Proceedings of the National Academy of Sciences of the United States of America
Proceedings of the National Academy of Sciences of the United States of America
Proceedings of the National Academy of Sciences of the United States of America
Plastic and Reconstructive Surgery
Proceedings of the National Academy of Sciences of the United States of America
The Journal of Experimental Medicine
Hepatology
Molecular Biology of the Cell
Hepatology (Baltimore, Md.)
Faseb Journal
Hepatology (Baltimore, Md.)
Cancer Research
Cancer Research
Cancer Research
The Journal of Urology
Nature Communications
Cancer Research
The Journal of Urology
Cancer Research
International Journal of Radiation Oncology, Biology, Physics
The Journal of Urology
International Journal of Radiation Oncology, Biology, Physics
American Journal of Hematology
The Journal of Urology
Cancer Research
Cancer Research
Blood
Cancer Research
Molecular Genetics of Dysregulated pH Homeostasis
Molecular Genetics of Dysregulated pH Homeostasis
DCI Centers, Cancer Types & Labs
Offices & Contact
Durham, NC
27708 Duke Box 3382
Durham, NC
27710