Our lab focuses on understanding how metabolic networks are coordinated to promote cell growth in physiological and disease states, and how to leverage that understanding to exploit metabolic dependencies in cancer. For cells to proliferate, they must first duplicate their biomass through activation of complex and highly coordinated biosynthetic programs. Such programs are regulated by signaling pathways that stimulate metabolic networks in response to growth-promoting cues. However, the exact nature and extent of metabolic control by specific signaling pathways, as well as the underlying molecular mechanisms that link signaling to metabolism, remain poorly defined. This is especially true in cancer, where oncogenic driver mutations uncoupling signaling and metabolic outputs from their normal regulatory inputs, resulting in extensive metabolic reprogramming that promotes rapid, uncontrolled cell growth. Although this provides a growth advantage, locking pathways in the "on" state can come at the cost of reduced plasticity and increased dependence on specific nutrients, enzymes or pathways for sustained growth and viability. Thus the uniquely reprogrammed metabolic networks in cancer cells offer an opportunity to identify and target metabolic processes that are uniquely essential in those cells.
To exploit these “metabolic vulnerabilities”, our laboratory seeks to understand how signaling pathways coordinate metabolic networks, and the impact of common oncogenic mutations. We combine metabolomics, metabolic flux analysis, expression profiling, and mechanistic studies to gain a comprehensive understanding of how signaling pathways remodel cellular metabolism. Emphasis on in vivo models, in addition to mechanistic cell culture studies, is particularly important, as we currently lack sufficient understanding of which nutrients and metabolic precursors limit cell growth in physiological and tumor microenvironments. By leveraging these novel insights, we seek to identify unique cancer dependencies that can be translated into new therapeutic approaches.