db Home Program in Developmental Biology BCM Home
Baylor College of Medicine
Previous Faculty List Next

Thomas Westbrook

Thomas (Trey) F. Westbrook

E-mail: thomasw@bcm.edu

Assistant Professor, Baylor College of Medicine

B.S., Allegheny College, Meadville, PA, 1997
Ph.D., University of Rochester School of Medicine, Rochester, NY, 2003
Postdoc, Harvard Medical School, Boston, MA, 2003-07


RNAi-based strategies to cancer gene discovery; REST tumor suppressor pathway

Cancers are driven by genomic and epigenetic alterations that result in the activation of cellular proto-oncogenes and the inactivation of tumor suppressor genes. Although high-throughput genomic approaches have begun to establish extensive catalogs of gene alterations in human tumors, the genes that control tumor genesis, progression, and response to therapies are often concealed by the complex chromosomal instability in cancer cell genomes. This challenge is exacerbated by the lack of functional annotation for the vast majority of genes in the human genome. Thus, functional approaches are critical for identifying the genetic programs underlying cancer pathogenesis. Our laboratory applies genome-wide RNA interference (RNAi) and other technologies to the unbiased discovery of cancer genes and networks. Specifically, we focus on 4 areas of cancer gene discovery:

Discovering new oncogene-induced "stress pathways" and translating these pathways into cancer therapies

The cancer community has largely studied the effects of oncogenes and tumor suppressors and how they contribute to the "pro-tumorigenic" hallmarks of cancer cells. However, it's also become clear that oncogenes themselves induce a variety of stresses in cancer cells such as metabolic reprogramming, oxidative pressures, mitotic instability, and proteomic imbalance. These stress phenotypes, sometimes collectively referred to as oncogenic stress, can serve to antagonize tumor growth and survival. The idea that oncogenes confer a highly stressed state onto cancer cells predicts that strategies to exacerbate one or more of these oncogene-induced stresses could conceivably tilt this balance in favor of killing cancer cells. We have been interested in exploiting the idea of oncogene-induced stresses for therapeutic discovery by tackling 3 poorly understood questions: (1) what are the molecular mechanisms by which prominent oncogenes (ex. Myc, Ras, etc.) induce these stresses? (2) how do cancer cells tolerate these stresses? and (3) are these stress support pathways different in normal and tumor cells? By using forward genetic approaches, we have made surprising discoveries about the endogenous cell pathways that are required to tolerate predominant oncogenic drivers like c-Myc (ex. Kessler et al, Science 2012). We are now extending these studies by elucidating the stress support pathways that enable cancer cells to tolerate other prominent drivers.

Repositioning anti-cancer therapies for triple-negative breast cancer

Breast cancer is a collection of diseases with distinct clinical behaviors and heterogeneous molecular features. Among these disease subtypes, triple-negative breast cancer (TNBC) is the most aggressive, and the molecular determinants of TNBC are poorly understood. Recently, our group discovered a new tumor suppressor network that is disrupted in more than 70% of TNBCs (Sun et al, Cell 2011), with the tyrosine phosphatase PTPN12 acting as a core component of this network. Importantly, disruption of this tumor suppressor network leads to the concerted hyper-activation of a class of receptor tyrosine kinases. These kinases work together to drive TNBC and probably other cancers. Importantly, we have shown that pharmcologic inhibition of these collaborating kinases leads to tumor regression of primary TNBCs in vivo. We are currently dissecting the mechanism(s) by which these signaling pathways cooperate, and translating these discoveries into new clinical trials for TNBC patients at BCM.

Identifying new oncogene / tumor suppressor networks via functional genetic screens

With the explosion of genomic data emerging from TCGA, COSMIC, and other annotations of cancer genomes, there are fundamental challenges in (1) discerning which mutant genes are critical cancer drivers, (2) how are these drivers connected in genetic / signaling networks, and (3) are there key drivers that have not been uncovered by these genomic analyses. We are addressing these important questions by developing genetic screens in human and mouse systems for new tumor suppressors and oncogenes. By combining new genetic technologies and engineered cell systems, we are uncovering new signaling networks that control tumor initiation and progression. For instance, a series of our genetic screens in breast cancer have uncovered an interconnected network of over 40 new tumor suppressor (PTPN12, REST, INPP4B, etc.) and oncogenes (PLK1, TEX14, etc.) with unappreciated roles in human cancer (ex. Westbrook et al, Nature 2008; Sun et al., Cell 2011; Pavlova et al., eLife 2013). We are systematically applying genetic, cell biologic, and biochemical approaches to understand the functions of these gene networks in controlling malignant transformation.

Understanding drug resistance in breast cancer

Targeted therapies have revolutionized cancer treatment. These new medicines antagonize the survival and progression of tumors by inhibiting cancer-driving oncogenes. However, despite the early success of these therapies, there is substantive heterogeneity in the initial and long-term response of tumors to these therapies. A major goal in our group is to discover the mechanisms governing how tumors respond to targeted therapies and translating these discoveries into better ways of predicting patient response. Using new genetic screening technologies and methods, we have developed an approach to identify signaling networks that govern how cancer cells respond to targeted therapies. By using this approach, we are dissecting both the mechanisms of drug-action and pathways to resistance for agents that are in the clinic as well as drugs soon to be approved as new cancer therapies.


Selected Publications

Schlabach MR, Luo J, Solimini NL, Hu G, Xu Q, Li MZ, Zhao Z, Smogorzewska A, Sowa ME, Ang XL, Westbrook TF, Liang AC, Chang K, Hackett JA, Harper JW, Hannon GJ, Elledge SJ (2008) Cancer proliferation gene discovery through functional genomics. Science 319:620-624.

Westbrook TF, Hu G, Ang XL, Mulligan P, Pavlova NN, Liang A, Leng Y, Maehr R, Shi Y, Harper JW, Elledge SJ (2008) SCFβ-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature 452:370-374.

Mulligan P, Westbrook TF, Ottinger M, Pavlova N, Chang B, Macia E, Shi YJ, Barretina J, Liu J, Howley PM, Elledge SJ, Shi Y (2008) CDYL bridges REST and histone methyltransferases for gene repression and suppression of cellular transformation. Molecular Cell 32:718-726.

Luo J, Emanuele MJ, Li D, Creighton CJ, Schlabach MR, Westbrook TF, Wong KK, Elledge SJ (2009) A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137:835-848.

Sun T, Aceto N, Meerbrey KL, Kessler JD, Zhou C, Migliaccio I, Nguyen DX, Pavlova NN, Botero M, Huang J, Bernardi RJ, Schmitt E, Hu G, Li MZ, Dephoure N, Gygi SP, Rao M, Creighton CJ, Hilsenbeck SG, Shaw CA, Muzny D, Gibbs RA, Wheeler DA, Osborne CK, Schiff R, Bentires-Alj M, Elledge SJ, Westbrook TF (2011) Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase. Cell 144:703-718.

Meerbrey KL, Hu G, Kessler JD, Roarty K, Li MZ, Fang JE, Herschkowitz JI, Burrows AE, Ciccia A, Sun T, Schmitt EM, Bernardi RJ, Fu X, Bland CS, Cooper TA, Schiff R, Rosen JM, Westbrook TF*, Elledge SJ* (2011) The pINDUCER lentiviral toolkit for inducible RNA interference in vitro and in vivo. Proceedings of the National Academy of Sciences USA 108:3665-3670. (*equal contribution)

Kessler JD, Kahle KT, Sun T, Meerbrey KL, Schlabach MR, Schmitt EM, Skinner SO, Xu Q, Li MZ, Hartman ZC, Rao M, Yu P, Dominguez-Vidana R, Liang AC, Solimini NL, Bernardi RJ, Yu B, Hsu T, Golding I, Luo J, Osborne CK, Creighton CJ, Hilsenbeck SG, Schiff R, Shaw CA, Elledge SJ, Westbrook TF (2012) A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science 335:348-353.

Pei Y, Moore CE, Wang J, Tewari AK, Eroshkin A, Cho YJ, Witt H, Korshunov A, Read T, Sun JL, Schmitt EM, Miller CR, Buckley AF, McLendon RE, Westbrook TF, Northcott PA, Taylor MD, Pfister SM, Febbo PG, Wechsler-Reya RJ (2012) An animal model of Myc-driven medulloblastoma. Cancer Cell 21:155-167.

Pavolova N, Pallasch C, Elia A, Westbrook TF, Hemann M, Elledge SJ (2013) A Role for PVRL4-driven cell-cell interactions in tumorigenesis. eLife 2:e00358.

Park J, Al-Ramahi I, Mollema N, Kang H, Lagalwar S, Duvick L, Lee Y, Tan Q, Lu H-C, Jafar-Nejad P, Richman R, Liu X, Boudreau RL, Davidson BL, Shaw CA, Orr HT*, Westbrook TF*, Botas J*, Zoghbi HY* (2013) RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 498:325-331. (*equal contribution)

Cheung WKC, Zhao M, Liu Z, Stevens LE, Cao PD, Fang J, Westbrook TF, Nguyen DX (2013) Control of alveolar differentiation by the lineage transcription factors GATA6 and HOPX inhibits lung adenocarcinoma metastasis. Cancer Cell 23:725-738.


Contact Information

Thomas (Trey) F. Westbrook, Ph.D.
Department of Biochemistry and Molecular Biology
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza 304B
Houston, Texas 77030, U.S.A.

Tel: (713) 798-5364
Fax: (713) 796-9438
E-mail: thomasw@bcm.edu

Previous Faculty List Next