RAS-PI3K Pathway in CAFs Shapes Physicochemical Properties of Tumor ECM and restrains Tumor progression

Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment, promoting tumor progression through extracellular matrix (ECM) remodeling and paracrine signaling, but the signaling pathways controlling CAF function remain incompletely defined. Here, we demonstrate that RAS-PI3K signaling plays a central role in CAF activation and ECM remodeling by promoting collagen crosslinking, fibronectin organization, and glycoprotein deposition at least partially through the activation of YAP. Disruption of RAS-PI3K interaction in CAFs leads to structurally and mechanically defective ECMs that impair tumor cell adhesion, migration, and proliferation. In vivo , fibroblast-specific deletion of RAS-PI3K reduces tumor burden in different models of KRAS-driven lung cancer, limits ECM deposition, and enhances the response to chemotherapy in lung adenocarcinoma models. These findings position RAS-PI3K signaling as a critical regulator of CAF function and ECM remodeling, highlighting a drug repurposing therapeutic strategy to disrupt tumor-stroma interactions and improve treatment outcomes.