Stiffness‐Activated Stellate Cells Drive Pancreatic Cancer Liver Colonization via GMFG‐TNS4 Signaling

ABSTRACT Liver metastasis remains the primary cause of death in pancreatic cancer. Collagen deposition by activated hepatic stellate cells (HSCs) generates a stiff fibrotic niche that favors metastatic colonization, yet the underlying mechanisms remain incompletely understood. Using stiffness‐tunable hydrogels, it is shown that elevated substrate stiffness activates HSCs and establishes a self‐reinforcing loop of matrix stiffening. Mechanistically, stiffness triggers Piezo1‐mediated Ca 2 + influx, induces endoplasmic reticulum stress (ERS), and activates the IRE1α‐XBP1 pathway to upregulate glia maturation factor gamma (GMFG) transcription and secretion. GMFG is transported into pancreatic cancer cells where it binds to intracellular tensin‐4 (TNS4), promoting FAK/AKT phosphorylation and coordinating two programs critical for metastatic outgrowth: enhanced cell‐ECM adhesion and increased de novo fatty acid synthesis. In mice with graded liver stiffness, pharmacological inhibition of mechanosensitive cation channels reduces metastatic burden and dampens GMFG‐associated epithelial and lipogenic features, while targeting the GMFG‐TNS4 axis suppresses early hepatic micrometastatic seeding and long‐term liver metastasis burden. Together, these findings define a mechano‐ER stress‐paracrine cascade linking fibrotic stiffness to pro‐colonization signaling, highlighting the Piezo1‐GMFG‐TNS4 pathway as a therapeutic vulnerability in PDAC liver metastasis.