PINCH-1-dependent regulation on tumor matrix microenvironment in pancreatic cancer

Cancer-associated fibroblasts (CAFs) are vital in advancing pancreatic ductal adenocarcinoma (PDAC) cancer growth and fibrosis. Although their roles are recognized, the precise molecular mechanisms remain incompletely understood. The study focuses on PINCH-1, a molecule elevated in various tumors, and its lesser-known effects on tumor stromal cells. This work reveals that PINCH-1 ablation in pancreatic CAFs (P-CAFs) significantly reduces extracellular matrix (ECM) expression, particularly collagen I and fibronectin. For collagen I, this effect is due to PINCH-1's ability to stabilize Notch1 protein, preventing Notch1 degradation, which is crucial for collagen I production. Reintroducing PINCH-1 can reverse collagen I reduction, highlighting a novel mechanism for matrix remodeling through the PINCH-1-Notch1 axis. Moreover, PINCH-1 also boosts cancer cell proliferation via the AKT signaling pathway, as demonstrated in both in vitro and in vivo experiments. We identify PINCH-1 as a master regulator within P-CAFs that promotes PDAC progression through dual mechanisms: (1) sustaining desmoplasia via Notch1-dependent collagen I production and (2) fueling cancer cell proliferation via AKT activation. Targeting the PINCH-1/Notch1/AKT axis presents a novel theragnostic strategy to simultaneously disrupt the fibrotic tumor microenvironment and inhibit tumor growth in PDAC. (188 words).