Nutrient availability-driven changes in extracellular matrix biochemical and mechanical properties regulate pancreatic cancer cell biology

The extracellular matrix (ECM) provides key biochemical and biomechanical cues that govern fundamental cellular processes, including growth and migration. ECM dysregulation and altered cell-matrix interactions are a driver of cancer progression, exemplified by pancreatic ductal adenocarcinoma (PDAC), where an abnormally dense, collagen-rich, and stiff ECM correlates with poor patient outcomes. The PDAC microenvironment is poorly perfused, resulting in altered nutrient availability, yet how this metabolic stress shapes the ECM and its biological activity remains poorly understood. Herein, we demonstrate that glutamine, a key amino acid depleted in poorly perfused PDAC regions, regulates the biochemical composition, mechanical properties, and biological activity of fibroblast-derived ECM. As glutamine availability increases, fibroblasts shift from producing a basement membrane-like ECM toward an interstitial, mature ECM enriched in fibrillar collagens. The ECM generated under glutamine-rich conditions is stiffer, which limits PDAC cell growth, while simultaneously, the elevated collagen I content promotes migration in a 3D spheroid model. Mechanistically, glutamine-dependent collagen I engages integrin α2 (ITGA2) to activate focal adhesion kinase signaling, driving PDAC cell migration independent of growth. In PDAC patients, glutamine stress inversely correlates with collagen expression in CAFs, with collagen I-ITGA2 as the most enriched ECM receptor interaction pair compared to the normal pancreas. These findings establish nutrient availability as a key regulator of ECM biology and offer new avenues to therapeutically intervene with dysregulated cell-matrix interactions in PDAC.