Our laboratory is working to understand how metabolism supports cell physiology. We are defining how environmental factors impact metabolism at the cell, tissue, and organism level, and identifying aspects of metabolism that are limiting for cell proliferation in different contexts. Ultimately, we aim to translate our understanding of cancer cell metabolism into novel cancer therapies.
Complex regulatory mechanisms enable metabolism to match cell demands, which extend beyond the production of ATP. To proliferate, cells must transform available nutrients into the varied array of macromolecules that are needed to build a new cell. Despite extensive knowledge about metabolic pathways, and the recognition that metabolism changes are a universal feature of cancer, fundamental questions remain with respect to how different cancers repurpose metabolism to acquire the materials needed for tumor growth. Understanding which products of metabolism are limiting for proliferation, and how cancer cells obtain them in physiological tissue environments, is crucial to exploit metabolism for therapy. Our long-term goal is to understand how mammalian cell metabolism supports cell physiology in normal and disease states with a near-term focus on how metabolism supports cancer cell proliferation.
The metabolic phenotypes of proliferating cells are typically interpreted with an emphasis on either energy generation or how signaling events affect cell metabolism. This has led many to focus on how cancer genetics influences metabolic pathway use. We take a different approach that identifies limiting metabolic processes, considers how these are constrained by the extracellular environment, and defines how metabolic limitations are overcome within a physiological tissue context. Using mass spectrometry to trace nutrient fate in systems with altered metabolic regulation, and manipulating culture conditions to understand the effect of environment on metabolism, we generate hypotheses for how cells acquire key biomass components to support proliferation. We leverage our knowledge of metabolism to test these hypotheses using cell culture systems and mouse models. Coupling these approaches with biochemical assays and metabolite measurements, we aim to define how nutrient availability, metabolic pathway regulation, and tissue context constrain how cells use available materials to proliferate.
Our current interests include identifying which products of metabolism create bottlenecks for cell proliferation and understanding how different cancers repurpose metabolism to enable tumor growth. We are also interested in how diet and whole body metabolism influence cell metabolism in tissues to modify cancer and other disease phenotypes. Through our work, we aim to advance understanding of metabolic pathway biochemistry and its relationship to cancer and mammalian physiology.