Current Research in the Westbrook Lab

Understanding the fundamental basis of tissue specificity in cancer

It has long been recognized that cancers arising in different sites throughout the body show a tissue-specific pattern of driver mutations. This phenomenon has been further elucidated by recent large-scale efforts to sequence cancer genomes, such as The Cancer Genome Atlas (TCGA), which have revealed that alterations in many prominent cancer drivers (e.g. KRAS, BRAF, SF3B1) are restricted to specific tissues. With this wealth of data, there remain fundamental challenges in (1) discerning the mechanisms that underlie the tissue-specific patterns of cancer driver mutations, and (2) discovering how tissue context controls the vulnerabilities and synthetic lethalities of cancer.  We are addressing these questions through multi-omic profiling and functional genetic screening in human and mouse systems. Our genetic screens and proteogenomic characterization have uncovered novel networks of tumor suppressors and oncogenes that govern tissue-specific behavior of cancer and represent entry points for novel therapies (exs. Nair et al, Nature Medicine ; Sack et al, Cell ; Krug et al, Cell). We are working with academic and pharma/biotech partners to translate these discoveries into patient benefit.

Translating dysregulated RNA splicing in cancer into novel therapeutic approaches

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. A major goal in our laboratory is to systematically discover the stresses imposed by commonly mutated oncogenes as well as the pathways tumors require to tolerate these stresses. 

Through integrative genetics, computational biology, and chemical biology approaches, our team has discovered that many oncogenes cause synthetic lethality with components of RNA splicing, RNA decay, and other steps in RNA processing (ex. Kessler et al, Science; Hsu et al, Nature; Einstein et al, Molecular Cell; Bowling et al, Cell).  This results in many cancer types being hypersensitive to modest perturbations in RNA splicing and has led to therapeutic programs exploiting these unique cancer vulnerabilities.  Currently, we are investigating: (1) what are the molecular mechanisms by which prominent oncogenes (ex. Myc, Ras, etc.) induce stresses on RNA processing? (2) how do cancer cells tolerate these stresses? and (3) how does dysregulation in RNA processing regulate interactions between cancer and the immune system?