Abstract A032: Interstitial insulin enrichment drives pancreatic cancer growth by enhancing cancer cell metabolic plasticity

Abstract Metabolic diseases, such as type 2 diabetes, insulin resistance, and obesity, often coexist with pancreatic ductal adenocarcinoma (PDAC) and predict poor survival. Using a mouse model of diet-induced obesity, we showed that a high-fat diet (HFD) consumption that induces hyperinsulinemia, but not hyperglycemia, in mice accelerated the growth of xenografted patient-derived PDAC organoids (PDOs). Strikingly, even in the fasting state, insulin was highly enriched in the tumor interstitial fluid of pancreatic tumors under HFD. Modelling this elevated interstitial insulin concentration in vitro significantly increased PDO growth regardless of glucose levels. Mechanistically, chronic high-insulin exposure robustly enhances metabolic plasticity and nutrient utilization in PDOs by selectively upregulating distinct metabolic pathways in response to differences in extracellular glucose levels. Thus, the presence of robust insulin levels continuously supports tumor growth as glucose availability changes. Specifically, under low-glucose conditions, elevated insulin activates nutrient uptake machinery and amino acid metabolism, whereas it promotes aerobic glycolysis in high-glucose conditions. Pharmacological inhibition of these metabolic pathways attenuated insulin-mediated growth. Our study identifies insulin enrichment in the tumor-interstitial fluid as an important driver of metabolic adaptation in PDAC cells. Citation Format: Jeffrey SH. Lin, James D. Johnson, Christoph H. Borchers, David F. Schaeffer, Janel L. Kopp. Interstitial insulin enrichment drives pancreatic cancer growth by enhancing cancer cell metabolic plasticity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A032.