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

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.