Abstract 139: The nutrient-dictated ECM regulates cancer cell growth via the itga2-FAK-YAP axis

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. PDAC tumors are characterized by a dense desmoplastic stroma and altered nutrient availability that promote aggressive cancer cell behavior. A collagen-rich extracellular matrix (ECM) produced by cancer-associated fibroblasts (CAFs) is a key feature of PDAC’s stroma and associated with tumor progression and therapy resistance. How altered nutrient availability and ECM production are integrated to modulate PDAC cell biology is not well understood. To address this gap, we develop a spheroid outgrowth assay on ECM produced by CAFs under altered availability of glutamine, an amino acid shown to be depleted in PDAC. We find that glutamine availability dictates the composition of CAF-derived ECM. The glutamine-dictated ECM differentially modulates PDAC cell behavior, with ECM produced under high glutamine (HQ) availability restraining PDAC cell growth but promoting PDAC cell migration. We link these phenotypes to collagen I abundance, which is depleted in ECM produced under low glutamine (LQ) availability. Mechanistically, we find that increased stiffness of HQ ECM underlies its growth restraining properties, while its activation of focal adhesion kinase (FAK) signaling in PDAC cells supports migration. Specifically, collagen I in HQ ECM binds to integrin α2 (Itga2), activating FAK and downstream YAP/TAZ signaling, both of which are required for PDAC cell migration. In contrast, LQ ECM fails to activate YAP/TAZ signaling in PDAC cells. Activation of YAP/TAZ signaling alone was sufficient to rescue PDAC cell migration on LQ ECM. These findings demonstrate that tumor nutrient availability alters ECM composition, which modulates PDAC biology via Itga2-FAK-YAP signaling. Citation Format: Kristof Turan, Julien Guillard, Simon Schwoerer. The nutrient-dictated ECM regulates cancer cell growth via the itga2-FAK-YAP axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 139.