Taslim A. Al-Hilal, Maria-Anna Chrysovergi, Paula E. Grasberger, Fei Liu, Vera Auernheimer, Yan Zhou, Zebin Xiao, Mark Anthony Leon-Duque, Alba Santos, Tamanna Islam, Matteo Ligorio, Delphine Sicard, Clemens K. Probst, Vladimir Vrbanac, Tejaswini S. Reddi, Ludovic Vincent, Cassandra Happe, Edward Chaum, Charles R. Yates, Kaveh Daneshvar, Allan C. Mullen, David Ting, Eric S. White, Raghu Kalluri, Christina M. Woo, Ellen Puré, Wolfgang H. Goldmann, Jose Luis Alonso, Andrew M. Tager, Adam J. Engler, Daniel J. Tschumperlin, David Lagares
{"title":"Durotaxis是肺纤维化和转移性胰腺癌的驱动因子和潜在治疗靶点","authors":"Taslim A. Al-Hilal, Maria-Anna Chrysovergi, Paula E. Grasberger, Fei Liu, Vera Auernheimer, Yan Zhou, Zebin Xiao, Mark Anthony Leon-Duque, Alba Santos, Tamanna Islam, Matteo Ligorio, Delphine Sicard, Clemens K. Probst, Vladimir Vrbanac, Tejaswini S. Reddi, Ludovic Vincent, Cassandra Happe, Edward Chaum, Charles R. Yates, Kaveh Daneshvar, Allan C. Mullen, David Ting, Eric S. White, Raghu Kalluri, Christina M. Woo, Ellen Puré, Wolfgang H. Goldmann, Jose Luis Alonso, Andrew M. Tager, Adam J. Engler, Daniel J. Tschumperlin, David Lagares","doi":"10.1038/s41556-025-01697-8","DOIUrl":null,"url":null,"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. Al-Hilal, Chrysovergi et al. identify a role for durotaxis in lung fibrosis and metastatic pancreatic cancer, mediated by the FAK–paxillin mechanosensor complex, and demonstrate therapeutic targeting of this pathway using the small molecule JP-153.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1543-1554"},"PeriodicalIF":19.1000,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01697-8.pdf","citationCount":"0","resultStr":"{\"title\":\"Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer\",\"authors\":\"Taslim A. Al-Hilal, Maria-Anna Chrysovergi, Paula E. Grasberger, Fei Liu, Vera Auernheimer, Yan Zhou, Zebin Xiao, Mark Anthony Leon-Duque, Alba Santos, Tamanna Islam, Matteo Ligorio, Delphine Sicard, Clemens K. Probst, Vladimir Vrbanac, Tejaswini S. Reddi, Ludovic Vincent, Cassandra Happe, Edward Chaum, Charles R. Yates, Kaveh Daneshvar, Allan C. Mullen, David Ting, Eric S. White, Raghu Kalluri, Christina M. Woo, Ellen Puré, Wolfgang H. Goldmann, Jose Luis Alonso, Andrew M. Tager, Adam J. Engler, Daniel J. Tschumperlin, David Lagares\",\"doi\":\"10.1038/s41556-025-01697-8\",\"DOIUrl\":null,\"url\":null,\"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. 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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-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. Al-Hilal, Chrysovergi et al. identify a role for durotaxis in lung fibrosis and metastatic pancreatic cancer, mediated by the FAK–paxillin mechanosensor complex, and demonstrate therapeutic targeting of this pathway using the small molecule JP-153.
期刊介绍:
Nature Cell Biology, a prestigious journal, upholds a commitment to publishing papers of the highest quality across all areas of cell biology, with a particular focus on elucidating mechanisms underlying fundamental cell biological processes. The journal's broad scope encompasses various areas of interest, including but not limited to:
-Autophagy
-Cancer biology
-Cell adhesion and migration
-Cell cycle and growth
-Cell death
-Chromatin and epigenetics
-Cytoskeletal dynamics
-Developmental biology
-DNA replication and repair
-Mechanisms of human disease
-Mechanobiology
-Membrane traffic and dynamics
-Metabolism
-Nuclear organization and dynamics
-Organelle biology
-Proteolysis and quality control
-RNA biology
-Signal transduction
-Stem cell biology