My research goals are centered on three overarching themes:
How do the constellations of mutations present within each tumor influence its behavior? In particular, what are the functional consequences of specific tumor-associated mutations, in isolation or in combination with other genetic alterations? To explore this, I aim to combine genetic mouse models and multiplexed CRISPR screens to dissect the combinatorial and permutational complexity of cancer genomes.
What are the molecular mechanisms underlying tumor plasticity (e.g. transdifferentiation and dedifferentiation)? How can we block the ability of tumors to utilize these strategies and rapidly evolve resistance against therapies? To investigate these questions, I aim to develop controlled experimental systems for modeling the process of tumor plasticity, subsequently leveraging CRISPR screens to identify genetic factors that are critical for tumor lineage transformation.
Why are the genetic factors that promote resistance to T cell killing in vitro so rarely identified in patient cohorts undergoing immunotherapy? From better understanding this disconnect, can we rationally design new therapeutic approaches to increase the proportion of patients that respond to immunotherapy? To address these questions, I aim to dissect the in vivo immune response against tumors with deficits in pathways implicated in immunotherapy resistance in vitro, using single-cell and spatial transcriptomics approaches.