Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis

Nutrient limitation in the microenvironment of poorly perfused tumors constrains the metabolism of cancer cells. Identifying these microenvironmental constraints can provide new insight into the nutritional biochemistry of tumors and reveal metabolic liabilities of cancer cells. We have found that limitation of arginine in pancreatic cancers inhibits fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1. SREBP1-driven fatty acid synthesis produces saturated and monounsaturated fatty acids. Producing these fatty acids enables cells to maintain a balance of differently saturated fatty acids needed for lipid homeostasis, even upon exposure to environments enriched in one specific class of fatty acids. Given the constraints on lipid synthesis in the microenvironment, we asked if pancreatic cancers are sensitive to exposure to fats with imbalanced levels of saturated and unsaturated fats. We found microenvironmental constraints on lipid synthesis sensitize pancreatic cancer cells and tumors to exposure to fat sources that are enriched in polyunsaturated fatty acids. Thus, amino acid restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancer, which renders pancreatic tumors incapable of maintaining lipid homeostasis upon exposure to polyunsaturated-enriched fats. Mouse pancreatic cancer cells (mPDAC1) were grown in RPMI-1640 or in tumor interstitial fluid medium (TIFM), or in TIFM 1.19 mM arginine. Cells in each medium were grown with or without exogenous lipids using lipid stripped fetal bovine serium (FBS) for 24 hours in triplicate. After 24 hours, RNA was harvested and sent for library prep and sequencing.