Martin, Timothy D
Primary Appointment
Assistant Professor of Pharmacology, Pharmacology
Education
- BS, Chemistry, University of North Carolina
- PhD, Pharmacology, University of North Carolina
- Postdoc, Genetics, Harvard University
Contact Information
PO Box 800735, 1340 Jefferson Park Ave
Pinn Hall, Room 5224
Charlottesville, VA 22903
Telephone: 434-924-5454
Email: jhx2rz@virginia.edu
Research Disciplines
Biology, Cancer Biology, Cell and Developmental Biology, Genetics, Molecular Biology, Translational Science
Research Interests
Identifying tumor selective drug targets, Understanding the genetic drivers of tumor immune evasion
Research Description
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.