Metabolic Regulation of Cell Fate Decisions

Increasing evidence demonstrates that intracellular metabolic pathways can be critical drivers of tumor progression. Metabolites provide the biomass required for cancer cell proliferation and contribute to antioxidant defenses that promote survival and metastatic dissemination. Moreover, oncogenic mutations in several metabolic enzymes lead to accumulation of pathological levels of metabolites that interfere with histone and DNA demethylation and impose a block to differentiation. However, absent these specific mutations, whether the metabolic profile of cancer cells contributes to the establishment or maintenance of malignant cell identity remains poorly understood. Combining in vitro culture of cancer cells with mouse models of tumor progression, we define the metabolic changes driven by common oncogenes and tumor suppressors and elucidate how these metabolic alterations affect cancer-associated phenotypes. In particular, we focus on how metabolic alterations influence regulation of the chromatin landscape and expression of differentiation programs that antagonize tumor progression. These studies provide insight into the metabolic mechanisms through which tumor cells evade differentiation and sustain malignancy.