Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer
Durotaxis, cell migration along stiffness gradients, is linked to embryonic development, tissue repair and disease. 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)-paxillin interaction, a mechanosensory module that links stiffness cues to transcriptional programmes via YAP signalling. To probe this genetically, we generated a FAK-FAT<sup>L994E</sup> knock-in mouse, which disrupts FAK-paxillin binding, blocks durotaxis and attenuates disease severity. Pharmacological inhibition of FAK-paxillin 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.
Authors
- Vladimir Vrbanac (ORCID: https://orcid.org/0000-0002-0593-1723)
- Ellen Puré (ORCID: https://orcid.org/0000-0003-2107-3711)
- Raghu Kalluri (ORCID: https://orcid.org/0000-0002-2190-547X)
- David Tsai Ting (ORCID: https://orcid.org/0000-0002-3261-2322)
- Wolfgang H. Goldmann (ORCID: https://orcid.org/0000-0003-0738-2665)
- Clemens K. Probst (ORCID: https://orcid.org/0000-0002-5546-9143)
- Andrew M. Tager (ORCID: https://orcid.org/0000-0002-5826-918X)
- Charles R. Yates
- Paula Grasberger (ORCID: https://orcid.org/0000-0003-4241-081X)
- Tejaswini Reddi (ORCID: https://orcid.org/0000-0002-6616-9138)
- Alan C. Mullen (ORCID: https://orcid.org/0000-0002-4096-3106)
- José L. Alonso (ORCID: https://orcid.org/0000-0002-3146-8250)
- Tamanna Islam (ORCID: https://orcid.org/0000-0001-9067-4372)
- K. Daneshvar (ORCID: https://orcid.org/0000-0002-7863-0489)
- Adam Jeffrey Engler (ORCID: https://orcid.org/0000-0003-1642-5380)
- Vera Auernheimer
- Daniel J. Tschumperlin (ORCID: https://orcid.org/0000-0002-5115-9025)
- Delphine Sicard (ORCID: https://orcid.org/0000-0002-1062-6205)
- Ludovic G. Vincent
- Eric S. White (ORCID: https://orcid.org/0000-0003-4060-8443)
- Mark Anthony Leon Duque (ORCID: https://orcid.org/0000-0002-6894-2980)
- Christina M. Woo (ORCID: https://orcid.org/0000-0001-8687-9105)
- David Lagares (ORCID: https://orcid.org/0000-0002-7317-8796)
- Taslim A. Al‐Hilal (ORCID: https://orcid.org/0000-0002-9189-776X)
- Cassandra Happe
- Matteo Ligorio (ORCID: https://orcid.org/0000-0001-8865-0881)
- Yan Zhou (ORCID: https://orcid.org/0000-0002-8822-5276)
- Zebin Xiao (ORCID: https://orcid.org/0000-0002-3311-7403)
- Maria-Anna Chrysovergi (ORCID: https://orcid.org/0009-0007-4139-4666)
- Edward Chaum (ORCID: https://orcid.org/0000-0003-3542-8376)
- Fei Liu (ORCID: https://orcid.org/0000-0002-5774-310X)
- Alba Santos (ORCID: https://orcid.org/0000-0003-1949-3266)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Utah (US)
- University of Mississippi (US)
- Massachusetts General Hospital (US)
- 490 BioTech (United States) (US)
- Sanford Consortium for Regenerative Medicine (US)
- Innovation Research Center (US)
- La Jolla Bioengineering Institute (US)
- Mayo Clinic in Florida (US)
- Boehringer Ingelheim (United States) (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1038/s41556-025-01697-8
- Citations
- 12
- Primary Topic
- Cellular Mechanics and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 13.82