N‐cadherin Adhesive Interactions Mechanically Modulate Phenotype of Pancreatic Stellate Cells via YAP‐dependent Mechanosensing

Pancreatic ductal adenocarcinoma (PDAC) exhibits a dense desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs), which largely originate from pancreatic stellate cells (PSCs). Upon activation, PSCs promote extracellular matrix (ECM) remodeling and increase tissue stiffness, which in turn reinforces PSC activation via nuclear localization of Yes-associated protein (YAP), creating a self-sustaining fibrotic loop that facilitates tumor progression. Given the limited success of CAF depletion strategies, we explored whether PSC activation could be reversed through mechanical reprogramming via force-sensitive cadherin signaling. Here, we show a tunable polyethylene glycol (PEG)-based hydrogel system functionalized with RGD and HAVDI peptides to simulate varying matrix stiffness and N-cadherin ligation. We found that HAVDI-mediated N-cadherin ligation reduced the contractile state by disrupting the actin cap formation and nuclear flattening and thereby reducing nuclear YAP localization in PSCs, at intermediate stiffness (10-20 kPa). Furthermore, HAVDI-mediated reprogramming reversed PSC activation within a defined time window, suggesting that both matrix stiffness and mechanical dosing history critically determine reprogramming efficiency. Collectively, this study highlights a novel approach for CAFs reprogramming through mechanical modulation of cadherin signaling, offering new therapeutic potential in PDAC treatment.