Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer

Al-Hilal TA, Chrysovergi MA, Grasberger PE, Liu F, Auernheimer V, Zhou Y, Xiao Z, Leon-Duque MA, Santos A, Islam T, Ligorio M, Sicard D, Probst CK, Vrbanac V, Reddi TS, Vincent L, Happe C, Chaum E, Yates CR, Daneshvar K, Mullen AC, Ting D, White ES, Kalluri R, Woo CM, Puré E, Goldmann W, Alonso JL, Tager AM, Engler AJ, Tschumperlin DJ, Lagares D (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Nature Cell Biology Nature Research

Book Volume: 27

Pages Range: 1543-1554

Journal Issue: 9

DOI: 10.1038/s41556-025-01697-8

Abstract

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-FATL994E 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 with CRIS profile

Wolfgang Goldmann Lehrstuhl für Biophysik

Involved external institutions

Harvard University US United States (USA) (US) Mayo Clinic College of Medicine and Science (MCCMS) US United States (USA) (US) University of California, San Diego (UC San Diego, UCSD) US United States (USA) (US) Boehringer Ingelheim Pharma GmbH & Co. KG DE Germany (DE) Mass General Brigham US United States (USA) (US) University of Pennsylvania (UPenn) US United States (USA) (US) University of Utah US United States (USA) (US) Harvard T.H. Chan School of Public Health US United States (USA) (US) Massachusetts General Hospital US United States (USA) (US) Vanderbilt Eye Institute US United States (USA) (US) University of Mississippi (Ole Miss) US United States (USA) (US) University of Texas MD Anderson Cancer Center US United States (USA) (US)

How to cite

APA:

Al-Hilal, T.A., Chrysovergi, M.A., Grasberger, P.E., Liu, F., Auernheimer, V., Zhou, Y.,... Lagares, D. (2025). Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer. Nature Cell Biology, 27(9), 1543-1554. https://doi.org/10.1038/s41556-025-01697-8

MLA:

Al-Hilal, Taslim A., et al. "Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer." Nature Cell Biology 27.9 (2025): 1543-1554.

BibTeX: Download