Files
Abstract
Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to wellperfused tissues, nutrient deficits in tumors perturb cellular metabolic activity, which imposes metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising antineoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we measured the nutrient availability of LSL-KrasG12D/+; Trp53flox/flox; Pdx-1-Cre murine pancreatic tumors by extracting and analyzing interstitial fluid using quantitative metabolomic profiling. These measurements were used to make tumor interstitial fluid medium (TIFM), which we used to challenge pancreatic cancer cells with microenvironmental nutrient levels and analyze changes in cell metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1. As a result, we find arginine limitation causes pancreatic tumors to rely on lipid uptake to survive. Synthesis of monounsaturated and saturated fatty acids, along with providing lipids to the cell, is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids in cellular membranes. As a consequence of perturbed fatty acid synthesis due to arginine deprivation, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to polyunsaturated fatty acids, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to lipid deprivation and treatment with polyunsaturated-enriched fat sources.