Metabolic pathways are essential for maintaining cellular homeostasis, and in proliferative cells the demand to accumulate biomass requires metabolic pathway alteration. Indeed, altered bioenergetics is a hallmark of cancer. In contrast to normally proliferating cells, those within a tumor are frequently starved for nutrients due to a combination of increased nutrient consumption and unreliable tumor vasculature. Fluctuations in nutrient availability affect cancer cell metabolism, and may be part of a selective process that occurs during tumorigenesis. Thus, understanding both the altered metabolism of cancer cells and their response to nutrient deprivation will enable identification of metabolic liabilities that can be exploited for cancer therapy. My lab seeks to understand the pathways that are altered in cancer, the processes that these altered pathways support, and the environmental, genetic, and epigenetic contexts in which these pathways are important. To this end, my laboratory focuses on four key areas: (1) Serine biosynthesis and the key enzyme PHGDH, that we identified as over-expressed and required in ER-negative breast cancer. We will determine how this pathway supports tumor metabolism, and investigate the requirement for individual pathway components across cancer types. (2) Mutations in mitochondrially encoded oxidative phosphorylation subunits. We will investigate why such mutations persist in cancer and how they impact cellular metabolism. (3) Iron-cluster biosynthesis, the requirement for which we found to be dependent on environmental oxygen concentration. We will ask whether activation of this pathway is an important step in lung tumorigenesis. (4) Development of novel tools and approaches for future hypothesis generation. We are developing a strategy to assay broad classes of phenotypes across hundreds of cell lines simultaneously, as well as engaging in loss of function genetic screening upon restriction of key nutrients.