Professor, Department of Pathology and Director of the Center for Translational Research in the Molecular Genetics of Cancer, UCSF; Director for the Program in Cell Cycling and Signaling, UCSF Helen Diller Family Comprehensive Cancer Center
Research Summary
I have over 20 years of experience in studying human cells and the earliest responses to injury. I have lead multi-disciplinary P01 groups that address both the epithelial and stromal contributions to wound healing and malignancy. The model systems we have developed and the applied translational insights are perfectly suited for the proposed studies and have great potential to contribute to clinical utility. Our work was the first to develop biomarkers for risk stratification of ductal carcinoma in situ, a pre-malignant lesion of breast cancer. Our recent work has identified molecular aspects of stromal-epithelial stress responses and the interactions that facilitate tumor progression in breast and prostate. These analyses have enabled us to identify cell-extrinsic consequences of epithelial stress that lead to the activation of pro-tumorigenic stromal phenotypes. One of the most profound phenotypes involves the activation of a multicellular stromal program shared by high mammographic density and desmoplastic tumor tissues, characterized by repression of CD36. While studying these interactions we unexpectedly found a rare population of cells within disease-free tissue that has the potential to attain pluripotency. These cells have the ability to create functional tissues of all three germ layers which we hypothesize may be involved in metaplasia and inflammatory diseases. A single pluripotent cell can generate beating cardiomyocytes, lactating breast, bone, cartilage, vasculature, adipocytes, pancreas, and intestinal cells. We hypothesize that these cells may be the cell-of-origin for metaplastic adenocarcinoma of the breast and provide insights for the identification of novel therapeutic targets. Similarly, these cells may be responsible for a wide collection of phenotypes that are initiated by chronic stress and defective in a wide spectrum of cancers. Our studies are aimed at investigating the heterogenic tissue status of malignancies and developing interventions.
Education
University of South Florida, Tampa, FL, B.S., 1973, Zoology
Washington University, St. Louis, MO, Ph.D., 1980, Molecular Biology
Washington University, St. Louis, MO, 1976-1980, Predoctoral Fellow
Stanford University, Stanford, CA, 1981-1984, Postdoctoral Fellow
Stanford University, Stanford, CA, 1984-1985, Senior Research Associate
Professional Experience
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1974-1976
Ph.D. Candidate, Dept. of Pathology, University of North Carolina, Chapel Hill (transferred)
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1976-1980
Pre-doctoral Fellow in Program for Cellular & Molecular Biology, Washington University, St. Louis, Missouri (advisor, Dr. M. Lieberman)
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1980-1981
Postdoctoral Fellow in Dept. of Microbiology & Immunology, Washington Univ., St. Louis, MO
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1981-1985
Postdoctoral Fellow/Senior Research Associate in Department of Biological Sciences, Stanford University, Stanford, California (advisor, Dr. R.T. Schimke)
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1985-1994
Assistant/Associate Professor of Pathology and Member: UNC Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, North Carolina
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1994-Present
Professor of Pathology, Director of the Center for Translational Research in the Molecular Genetics of Cancer, Member: UCSF Comprehensive Cancer Center – Director for the Program in Cell Cycling and Signaling; Program in Biological Sciences (PIBS); Program in Biomedical Sciences (BMS), University of California at San Francisco, CA
Selected Publications
- Molinaro AM, Sison JD, Ljung BM, Tlsty TD, Kerlikowske K. Risk prediction for local versus regional/metastatic tumors after initial ductal carcinoma in situ diagnosis treated by lumpectomy. Breast Cancer Res Treat. 2016 Jun; 157(2):351-61.
View on PubMed - Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev. 2016 May 1; 30(9):1002-19.
View on PubMed - Kurup A, Ravindranath S, Tran T, Keating M, Gascard P, Valdevit L, Tlsty TD, Botvinick EL. Novel insights from 3D models: the pivotal role of physical symmetry in epithelial organization. Sci Rep. 2015; 5:15153.
View on PubMed - Drake CR, Estévez-Salmerón L, Gascard P, Shen Y, Tlsty TD, Jones EF. Towards aspirin-inspired self-immolating molecules which target the cyclooxygenases. Org Biomol Chem. 2015 Dec 7; 13(45):11078-86.
View on PubMed - Integrative analysis of 111 reference human epigenomes. Nature. 2015 Feb 19; 518(7539):317-30.
View on PubMed - Elliott G, Hong C, Xing X, Zhou X, Li D, Coarfa C, Bell RJ, Maire CL, Ligon KL, Sigaroudinia M, Gascard P, Tlsty TD, Harris RA, Schalkwyk LC, Bilenky M, Mill J, Farnham PJ, Kellis M, Marra MA, Milosavljevic A, Hirst M, Stormo GD, Wang T, Costello JF. Intermediate DNA methylation is a conserved signature of genome regulation. Nat Commun. 2015; 6:6363.
View on PubMed - Gascard P, Bilenky M, Sigaroudinia M, Zhao J, Li L, Carles A, Delaney A, Tam A, Kamoh B, Cho S, Griffith M, Chu A, Robertson G, Cheung D, Li I, Heravi-Moussavi A, Moksa M, Mingay M, Hussainkhel A, Davis B, Nagarajan RP, Hong C, Echipare L, O'Geen H, Hangauer MJ, Cheng JB, Neel D, Hu D, McManus MT, Moore R, Mungall A, Ma Y, Plettner P, Ziv E, Wang T, Farnham PJ, Jones SJ, Marra MA, Tlsty TD, Costello JF, Hirst M. Epigenetic and transcriptional determinants of the human breast. Nat Commun. 2015; 6:6351.
View on PubMed - Lowdon RF, Zhang B, Bilenky M, Mauro T, Li D, Gascard P, Sigaroudinia M, Farnham PJ, Bastian BC, Tlsty TD, Marra MA, Hirst M, Costello JF, Wang T, Cheng JB. Regulatory network decoded from epigenomes of surface ectoderm-derived cell types. Nat Commun. 2014; 5:5442.
View on PubMed - DeFilippis RA, Fordyce C, Patten K, Chang H, Zhao J, Fontenay GV, Kerlikowske K, Parvin B, Tlsty TD. Stress signaling from human mammary epithelial cells contributes to phenotypes of mammographic density. Cancer Res. 2014 Sep 15; 74(18):5032-44.
View on PubMed - Wu A, Liao D, Tlsty TD, Sturm JC, Austin RH. Game theory in the death galaxy: interaction of cancer and stromal cells in tumour microenvironment. Interface Focus. 2014 Aug 6; 4(4):20140028.
View on PubMed - Liao D, Tlsty TD. Evolutionary game theory for physical and biological scientists. I. Training and validating population dynamics equations. Interface Focus. 2014 Aug 6; 4(4):20140037.
View on PubMed - Liao D, Tlsty TD. Evolutionary game theory for physical and biological scientists. II. Population dynamics equations can be associated with interpretations. Interface Focus. 2014 Aug 6; 4(4):20140038.
View on PubMed - Wu A, Loutherback K, Lambert G, Estévez-Salmerón L, Tlsty TD, Austin RH, Sturm JC. Cell motility and drug gradients in the emergence of resistance to chemotherapy. Proc Natl Acad Sci U S A. 2013 Oct 1; 110(40):16103-8.
View on PubMed - Zhang B, Zhou Y, Lin N, Lowdon RF, Hong C, Nagarajan RP, Cheng JB, Li D, Stevens M, Lee HJ, Xing X, Zhou J, Sundaram V, Elliott G, Gu J, Shi T, Gascard P, Sigaroudinia M, Tlsty TD, Kadlecek T, Weiss A, O'Geen H, Farnham PJ, Maire CL, Ligon KL, Madden PA, Tam A, Moore R, Hirst M, Marra MA, Zhang B, Costello JF, Wang T. Functional DNA methylation differences between tissues, cell types, and across individuals discovered using the M&M algorithm. Genome Res. 2013 Sep; 23(9):1522-40.
View on PubMed - Xie M, Hong C, Zhang B, Lowdon RF, Xing X, Li D, Zhou X, Lee HJ, Maire CL, Ligon KL, Gascard P, Sigaroudinia M, Tlsty TD, Kadlecek T, Weiss A, O'Geen H, Farnham PJ, Madden PA, Mungall AJ, Tam A, Kamoh B, Cho S, Moore R, Hirst M, Marra MA, Costello JF, Wang T. DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape. Nat Genet. 2013 Jul; 45(7):836-41.
View on PubMed - López-Díaz FJ, Gascard P, Balakrishnan SK, Zhao J, Del Rincon SV, Spruck C, Tlsty TD, Emerson BM. Coordinate transcriptional and translational repression of p53 by TGF-ß1 impairs the stress response. Mol Cell. 2013 May 23; 50(4):552-64.
View on PubMed - Roy S, Gascard P, Dumont N, Zhao J, Pan D, Petrie S, Margeta M, Tlsty TD. Rare somatic cells from human breast tissue exhibit extensive lineage plasticity. Proc Natl Acad Sci U S A. 2013 Mar 19; 110(12):4598-603.
View on PubMed - Dumont N, Liu B, Defilippis RA, Chang H, Rabban JT, Karnezis AN, Tjoe JA, Marx J, Parvin B, Tlsty TD. Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia. 2013 Mar; 15(3):249-62.
View on PubMed - A physical sciences network characterization of non-tumorigenic and metastatic cells. Sci Rep. 2013; 3:1449.
View on PubMed - Fordyce CA, Patten KT, Fessenden TB, DeFilippis R, Hwang ES, Zhao J, Tlsty TD. Cell-extrinsic consequences of epithelial stress: activation of protumorigenic tissue phenotypes. Breast Cancer Res. 2012; 14(6):R155.
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