Alterations in the metabolism of cancer cells can directly promote growth and survival and create metabolic dependencies. Targeting these metabolic dependencies is an attractive strategy for designing novel anti-cancer therapies. The development of these treatments is hindered by a major gap in our understanding of how changes in cancer cell metabolism, and in particular lipid metabolism, alter sensitivity to cell death induced by chemotherapy. My goal is to mechanistically define the links between cancer-associated mutations, metabolic lipid reprogramming, and sensitivity to cell death. F99 Training: During my dissertation research, I investigated the genetic and metabolic factors mediating cancer cell sensitivity to ferroptosis, a form of non-apoptotic cell death that occurs due to metabolic stress. Ferroptosis occurs when cells are deprived of the essential intracellular antioxidant, glutathione, leading to the toxic, iron-dependent accumulation of lipid reactive oxygen species (ROS). I discovered that the canonical tumor suppressor p53 and its downstream transcriptional target CDKN1A (encoding p21), suppress ferroptosis by reprogramming glutathione metabolism and decreasing the accumulation of lipid ROS. From this work it remains unclear how the p53-p21 pathway reprograms glutathione metabolism. I hypothesize that the p53-p21 pathway promotes the regeneration of reduced glutathione from oxidized glutathione to block lipid ROS accumulation. I will test this hypothesis in vivo and in vitro using genetic and chemical tools, metabolic tracing analysis, and mouse cancer models. This training will allow me to develop the skills and experience necessary to secure and succeed in a postdoctoral position at a top laboratory studying cancer metabolism. K00 Training: Alterations in lipid metabolism are common in cancer and may directly facilitate growth and survival. How changes in lipid metabolism impact cancer cell sensitivity to chemotherapy- induced cell death is not well understood. A major challenge in answering this question is that lipid metabolism is highly responsive to environmental conditions, and in vitro tissue culture systems poorly recapitulate the specific lipid metabolic environment experienced by cancer cells exposed to human serum. During my postdoctoral training, I will address this critical problem by developing new tools to more closely mimic the in vivo lipid metabolic environment in cell culture. Using these tools, I will determine how reprogramming of lipid metabolism alters cancer cell sensitivity to chemotherapy-induced cell death using large-scale genetic and chemical approaches. The training of the K00 will enable me to gain the technical and professional skills necessary to achieve my long-term goal of becoming an independent cancer investigator.
The effects of metabolic reprogramming on cancer cell sensitivity to cell death remain poorly understood. During my predoctoral and postdoctoral training, I propose to investigate how reprogramming of glutathione and lipid metabolism regulates the sensitivity of cancer cells to cell death. These studies may help to identify new therapeutic strategies targeting the metabolic dependencies of cancer cells.
