PR002307 (Project)

Description:Nutrient limitation is a characteristic feature of poorly perfused tumors. These changes in nutrient availability impose metabolic constraints and perturb metabolic pathways in cancer cells, in contrast to cells in well-perfused tissues. Consequently, targeting the metabolic dependencies created by tumor microenvironmental constraints may be a promising antineoplastic therapeutic approach. To identify these adaptations, we challenged pancreatic cancer cell lines (mouse Pancreatic Ductal Adenocarcinoma - PDAC) with pathophysiological nutrient levels and analyzed changes to cell metabolism. Here, we report that arginine limitation in pancreatic cancer perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1. Synthesis of these acyl species is critical to maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids in cellular membranes. We found that, as a consequence of the loss of fatty acid synthesis, pancreatic cancer cells were unable to maintain balanced lipidomes when exposed to polyunsaturated fatty acids, leading to cell death by ferroptosis. Importantly, we found orally administering oils rich in polyunsaturated fats reduces tumor burden in mice with pancreatic cancer. In sum, this study illustrates that arginine restriction in the tumor microenvironment alters pancreatic cancer cells by perturbing lipid synthesis, making them sensitive to supplementation with polyunsaturated fats.