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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\u2010tunable hydrogels, it is shown that elevated substrate stiffness activates HSCs and establishes a self\u2010reinforcing loop of matrix stiffening. Mechanistically, stiffness triggers Piezo1\u2010mediated Ca\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    influx, induces endoplasmic reticulum stress (ERS), and activates the IRE1\u03b1\u2010XBP1 pathway to upregulate glia maturation factor gamma (GMFG) transcription and secretion. GMFG is transported into pancreatic cancer cells where it binds to intracellular tensin\u20104 (TNS4), promoting FAK\/AKT phosphorylation and coordinating two programs critical for metastatic outgrowth: enhanced cell\u2010ECM 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\u2010associated epithelial and lipogenic features, while targeting the GMFG\u2010TNS4 axis suppresses early hepatic micrometastatic seeding and long\u2010term liver metastasis burden. Together, these findings define a mechano\u2010ER stress\u2010paracrine cascade linking fibrotic stiffness to pro\u2010colonization signaling, highlighting the Piezo1\u2010GMFG\u2010TNS4 pathway as a therapeutic vulnerability in PDAC liver metastasis.\n                  <\/jats:p>","DOI":"10.1002\/advs.76173","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T19:26:39Z","timestamp":1781810799000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Stiffness\u2010Activated Stellate Cells Drive Pancreatic Cancer Liver Colonization via GMFG\u2010TNS4 Signaling"],"prefix":"10.1002","volume":"13","author":[{"given":"Biwen","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital and Medical School of Nantong University  Nantong China"},{"name":"Research Center of Clinical Medicine Affiliated Hospital and Medical 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