Our lab seeks to understand how carcinogenic conditions promote cancer evolution and to discover pathway dependencies in cancers that can be exploited therapeutically.           

For the former, we have developed an evolutionary based model for cancer development, Adaptive Oncogenesis. In this model, mutations (including oncogenic mutations) face fitness landscapes that vary with age or following carcinogen exposure. We propose that long-lived multicellular organisms have evolved stem cell populations with high fitness, not only as a means of efficiently maintaining a tissue, but also because high fitness in a cell population will oppose somatic evolution. Highly effective competition in a young healthy stem cell population serves to maintain the status quo, preventing somatic evolution.  But in stem cell pools damaged by aging, irradiation or other insults, the fitness landscape will be dramatically altered. The fitness of the stem cell pool will be reduced, promoting selection for mutations and epigenetic events that improve fitness.  Using mouse models and focusing on hematopoietic and lung tissues, we are currently exploring how reduced progenitor cell fitness resulting from aging and other insults can select for adaptive oncogenic events and thereby promote the expansion and fixation of oncogenically initiated cells.

Other studies in the lab are geared towards the development of novel therapeutic strategies to treat leukemias. We perform genome-wide loss-of-function screens using RNA interference (RNAi) and CRISPR to identify genes whose inhibition will synergize with current targeted therapeutics to eliminate leukemia cells.  These studies could lead to discovery of adjuvants to current therapies that will more effectively treat or possibly even cure leukemias.