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Despite solid in vitro evidence, its role in vivo remains largely speculative. Here we demonstrate that durotaxis actively drives disease progression in vivo in mouse models of lung fibrosis and metastatic pancreatic cancer. In lung fibrosis, durotaxis directs fibroblast recruitment to sites of injury, where they undergo mechano-activation into scar-forming myofibroblasts. In pancreatic cancer, stiffening of the tumour microenvironment induces durotaxis of cancer cells, promoting metastatic dissemination. Mechanistically, durotaxis is mediated by focal adhesion kinase (FAK)\u2013paxillin interaction, a mechanosensory module that links stiffness cues to transcriptional programmes via YAP signalling. To probe this genetically, we generated a FAK-FAT\n                    <jats:sup>L994E<\/jats:sup>\n                    knock-in mouse, which disrupts FAK\u2013paxillin binding, blocks durotaxis and attenuates disease severity. Pharmacological inhibition of FAK\u2013paxillin interaction with the small molecule JP-153 mimics these effects. Our findings establish durotaxis as a disease mechanism in vivo and support anti-durotactic therapy as a potential strategy for treating fibrosis and cancer.\n                  <\/jats:p>","DOI":"10.1038\/s41556-025-01697-8","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T09:06:24Z","timestamp":1757408784000},"page":"1543-1554","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer"],"prefix":"10.1038","volume":"27","author":[{"given":"Taslim 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The companies are developing treatments for organ fibrosis and cancer related to this work. D.L. has received consulting fees from Merck & Co, Scholar Rock, Ono Pharma, UCB Biopharma, Calico Life Sciences, Johnson & Johnson, Inzen Therapeutics, BioHope and PureTech Health LLC that are not related to this work. D.L. has received research support from Boehringer Ingelheim, Merck & Co, Indalo Therapeutics, Ono Pharma and Unity Biotechnology, which was not used in this work. D.J.T. is a scientific advisor and has a financial interest in Zenon Biotech. D.T. has received consulting fees from ROME Therapeutics, Foundation Medicine, Inc., NanoString Technologies, EMD Millipore Sigma and Pfizer that are not related to this work. D.T. is a founder and has equity in ROME Therapeutics, PanTher Therapeutics and TellBio, Inc., which is not related to this work. D.T. receives research support from ACD-Biotechne, PureTech Health LLC and Ribon Therapeutics, which was not used in this work. D.L.\u2019s and D.T.\u2019s interests were reviewed and are managed by Mass General Brigham in accordance with their conflict-of-interest policies. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}