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Timothy D Martin

Timothy D Martin

Assistant Professor of Pharmacology, Pharmacology

Primary Location
PO Box 800735, 1340 Jefferson Park Ave
Pinn Hall, Room 5224
Charlottesville, VA 22903
Primary Phone Number
434.924.5454
Email
[email protected]
Website
www.martinlabatuva.com

Bio & Overview

The major focus of my lab is to understand how the genetic drivers of cancer fuel tumor evolution and to mechanistically define how these genes contribute to various tumor phenotypes. Sporadic cancers are driven by mutation and amplification of oncogenes (OG) and loss of function mutation and deletion of tumor suppressor genes (TSGs). These genetic events ultimately lead to tumorigenesis, metastasis, and eventually, mortality. A comprehensive understanding of how these cancer drivers promote tumor evolution will enable more specific targeting of tumors for improved cancer therapies. My research has used unbiased genetic screening systems to address two main areas: 1) Identifying tumor selective vulnerabilities in cells harboring tumor drivers, and 2) Defining how different cancer drivers promote tumor immune evasion. 1) Classical oncogenic genetic events like activating point mutations in KRAS or amplification of MYC drive sporadic cancers. If we had the ability to potently and specifically target tumor cells with these OGs, we would have better anti-cancer therapies with reduced toxicity to non-tumor cells. Using combinations of whole genome CRISPR and essential gene shRNA libraries in isogenic cell lines differing only by the presence or absence of a tumor driver, my lab has identified many genes and protein networks required for either MYC amplified or KRAS mutant cell growth but are dispensable for normal cell growth. Future research including in vivo tumor systems will examine if these genes represent potential anti-cancer therapies. 2) Tumor evolution is a complex adaptive process that involves alterations in many cellular functions including cell differentiation status, telomere maintenance, cell proliferation control, adaptation to altered nutritional states, evolution of angiogenesis capabilities, avoidance of cell death, adaptation to proteotoxic and genomic stressors, etc. A major hurdle to tumor formation is the body’s immune system. The immune system can treat tumor as an emerging pathogen unleashing a response that aims to eliminate the tumor, thereby selecting for genetic alterations that result in immune surveillance adaptation. Understanding how different common cancer drivers contribute to immune system avoidance is still largely unknown. We’ve used syngeneic tumor models to perform CRISPR and cDNA-based genetic screens in vitro and as tumor transplants in vivo in both immunocompetent and immunocompromised mice that lack an adaptive immune system. The results from these experiments have identified both TSGs and OGs that contribute to tumor immune evasion. Current research in the lab aims to mechanistically understand how these genes affect tumor immune surveillance with the goal of reversing their effects helping to reignite the immune system to more effectively eliminate tumor cells.

Academic Information

Department
Pharmacology

Primary Education

  • BS, Chemistry, University of North Carolina, 2006
  • PhD, Pharmacology, University of North Carolina, 2013
  • Postdoc, Genetics, Harvard University, 2023

Research Interests

Identifying tumor selective drug targets, Understanding the genetic drivers of tumor immune evasion

Research Disciplines

  • Biology
  • Cancer Biology
  • Cell and Developmental Biology
  • Genetics
  • Molecular Biology
  • Molecular Pharmacology
  • Translational Science

Research Opportunities

  • Cancer Biology
  • Cancer Immunology and Immunotherapy
  • Genetics
  • Molecular Biology
  • Molecular Pharmacology

PhD Programs

  • Pharmacology

Selected Publications

2024

Journal article

Lam, I., Ndayisaba, A., Lewis, A. J., Fu, Y., Sagredo, G. T., Kuzkina, A., . . . Khurana, V. (2024). Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions. . Neuron, S0896-6273(24)00409-4. doi:10.1016/j.neuron.2024.06.002

Journal article

Hillis, A. L., Martin, T. D., Manchester, H. E., Högström, J., Zhang, N., Lecky, E., . . . Toker, A. (2024). Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer.. Cancer research. doi:10.1158/0008-5472.can-24-0970

Preprint

Martin, T. D., Watson, E. V., Choi, M. Y., Nabet, B., Gray, N. S., Xu, Q., & Elledge, S. J. (2024). Proteasomal control of anti-CRISPRs for the regulation of CRISPR/Cas9 activity using Cas9-ACROBAT.. doi:10.1101/2024.05.13.593596

Preprint

Martin, T., Choi, M. Y., Patel, R., Liang, A., Li, M., & Elledge, S. (2024). Identification of MYC synthetic lethal genes and networks. doi:10.1101/2024.04.25.590465

2022

Journal article

Oreskovic, E., Wheeler, E. C., Mengwasser, K. E., Fujimura, E., Martin, T. D., Tothova, Z., & Elledge, S. J. (2022). Genetic analysis of cancer drivers reveals cohesin and CTCF as suppressors of PD-L1. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 119(7). doi:10.1073/pnas.2120540119

2021

Journal article

Cook, D. R., Kang, M., Martin, T. D., Galanko, J. A., Loeza, G. H., Trembath, D. G., . . . Der, C. J. (2022). Aberrant Expression and Subcellular Localization of ECT2 Drives Colorectal Cancer Progression and Growth. CANCER RESEARCH, 82(1), 90-104. doi:10.1158/0008-5472.CAN-20-4218

Journal article

Naxerova, K., Di Stefano, B., Makofske, J. L., Watson, E. V., de Kort, M. A., Martin, T. D., . . . Elledge, S. J. (2021). Integrated loss- and gain-of-function screens define a core network governing human embryonic stem cell behavior. GENES & DEVELOPMENT, 35(21-22), 1527-1547. doi:10.1101/gad.349048.121

Journal article

Martin, T. D., Patel, R. S., Cook, D. R., Choi, M. Y., Patil, A., Liang, A. C., . . . Elledge, S. J. (2021). The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation. SCIENCE, 373(6561), 1327-+. doi:10.1126/science.abg5784

2018

Journal article

Sack, L. M., Davoli, T., Li, M. Z., Li, Y., Xu, Q., Naxerova, K., . . . Elledge, S. J. (2018). Profound Tissue Specificity in Proliferation Control Underlies Cancer Drivers and Aneuploidy Patterns. CELL, 173(2), 499-+. doi:10.1016/j.cell.2018.02.037

2017

Journal article

Martin, T. D., Cook, D. R., Choi, M. Y., Li, M. Z., Haigis, K. M., & Elledge, S. J. (2017). A Role for Mitochondrial Translation in Promotion of Viability in K-Ras Mutant Cells. CELL REPORTS, 20(2), 427-438. doi:10.1016/j.celrep.2017.06.061

2015

Journal article

Kang, C., Xu, Q., Martin, T. D., Li, M. Z., Demaria, M., Aron, L., . . . Elledge, S. J. (2015). The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. SCIENCE, 349(6255). doi:10.1126/science.aaa5612

Journal article

Gentry, L. R., Nishimura, A., Cox, A. D., Martin, T. D., Tsygankov, D., Nishida, M., . . . Der, C. J. (2015). Divergent Roles of CAAX Motif-signaled Posttranslational Modifications in the Regulation and Subcellular Localization of Ral GTPases. JOURNAL OF BIOLOGICAL CHEMISTRY, 290(37), 22851-22861. doi:10.1074/jbc.M115.656710

2014

Journal article

Gentry, L. R., Martin, T. D., Reiner, D. J., & Der, C. J. (2014). Ral small GTPase signaling and oncogenesis: More than just 15 minutes of fame. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 1843(12), 2976-2988. doi:10.1016/j.bbamcr.2014.09.004

Journal article

Martin, T. D., Chen, X. -W., Kaplan, R. E. W., Saltiel, A. R., Walker, C. L., Reiner, D. J., & Der, C. J. (2014). Ral and Rheb GTPase Activating Proteins Integrate mTOR and GTPase Signaling in Aging, Autophagy, and Tumor Cell Invasion. MOLECULAR CELL, 53(2), 209-220. doi:10.1016/j.molcel.2013.12.004

2013

Journal article

Neel, N. F., Stratford, J. K., Shinde, V., Ecsedy, J. A., Martin, T. D., Der, C. J., & Yeh, J. J. (2014). Response to MLN8237 in Pancreatic Cancer Is Not Dependent on RalA Phosphorylation. MOLECULAR CANCER THERAPEUTICS, 13(1), 122-133. doi:10.1158/1535-7163.MCT-12-1232

Journal article

Gentry, L. R., Martin, T. D., & Der, C. J. (2013). Mechanisms of Targeted Therapy Resistance Take a De-TOR. CANCER CELL, 24(3), 284-286. doi:10.1016/j.ccr.2013.08.021

2012

Journal article

Martin, T. D., Mitin, N., Cox, A. D., Yeh, J. J., & Der, C. J. (2012). Phosphorylation by Protein Kinase Cα Regulates RalB Small GTPase Protein Activation, Subcellular Localization, and Effector Utilization. JOURNAL OF BIOLOGICAL CHEMISTRY, 287(18), 14827-14836. doi:10.1074/jbc.M112.344986

Journal article

Neel, N. F., Rossman, K. L., Martin, T. D., Hayes, T. K., Yeh, J. J., & Der, C. J. (2012). The RalB Small GTPase Mediates Formation of Invadopodia through a GTPase-Activating Protein-Independent Function of the RalBP1/RLIP76 Effector. MOLECULAR AND CELLULAR BIOLOGY, 32(8), 1374-1386. doi:10.1128/MCB.06291-11

Journal article

Martin, T. D., & Der, C. J. (2012). Differential involvement of RalA and RalB in colorectal cancer.. Small GTPases, 3(2), 126-130. doi:10.4161/sgtp.19571

2011

Journal article

Neel, N. F., Martin, T. D., Stratford, J. K., Zand, T. P., Reiner, D. J., & Der, C. J. (2011). The RalGEF-Ral Effector Signaling Network: The Road Less Traveled for Anti-Ras Drug Discovery.. Genes & cancer, 2(3), 275-287. doi:10.1177/1947601911407329

Journal article

Martin, T. D., Samuel, J. C., Routh, E. D., Der, C. J., & Yeh, J. J. (2011). Activation and Involvement of Ral GTPases in Colorectal Cancer. CANCER RESEARCH, 71(1), 206-215. doi:10.1158/0008-5472.CAN-10-1517

2010

Journal article

Vigil, D., Martin, T. D., Williams, F., Yeh, J. J., Campbell, S. L., & Der, C. J. (2010). Aberrant Overexpression of the Rgl2 Ral Small GTPase-specific Guanine Nucleotide Exchange Factor Promotes Pancreatic Cancer Growth through Ral-dependent and Ral-independent Mechanisms. JOURNAL OF BIOLOGICAL CHEMISTRY, 285(45), 34729-34740. doi:10.1074/jbc.M110.116756

Journal article

Kidd, A. R. I. I. I., Snider, J. L., Martin, T. D., Graboski, S. F., Der, C. J., & Cox, A. D. (2010). RAS-RELATED SMALL GTPASES RALA AND RALB REGULATE CELLULAR SURVIVAL AFTER IONIZING RADIATION. INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 78(1), 205-212. doi:10.1016/j.ijrobp.2010.03.023

Journal article

Wang, Q., Zimmerman, E. I., Toutchkine, A., Martin, T. D., Graves, L. M., & Lawrence, D. S. (2010). Multicolor Monitoring of Dysregulated Protein Kinases in Chronic Myelogenous Leukemia. ACS CHEMICAL BIOLOGY, 5(9), 887-895. doi:10.1021/cb100099h