An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR‐Addicted Lung Tumorigenesis
Abstract Despite epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), how it senses extracellular matrix (ECM) rigidity remain elusive in the context of the increasing role of tissue rigidity on various hallmarks of cancer developme...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202413443 |
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| author | Reza Bayat Mokhtari Divyaleka Sampath Paige Eversole Melissa Ong Yu Lin Dmitriy A. Bosykh Gandhi T.K. Boopathy Aravind Sivakumar Cheng‐Chun Wang Ramesh Kumar Joe Yeong Poh Sheng Ellen Karasik Barbara A. Foster Han Yu Xiang Ling Wenjie Wu Fengzhi Li Zoë Weaver Ohler Christine F. Brainson David W. Goodrich Wanjin Hong Sayan Chakraborty |
| author_facet | Reza Bayat Mokhtari Divyaleka Sampath Paige Eversole Melissa Ong Yu Lin Dmitriy A. Bosykh Gandhi T.K. Boopathy Aravind Sivakumar Cheng‐Chun Wang Ramesh Kumar Joe Yeong Poh Sheng Ellen Karasik Barbara A. Foster Han Yu Xiang Ling Wenjie Wu Fengzhi Li Zoë Weaver Ohler Christine F. Brainson David W. Goodrich Wanjin Hong Sayan Chakraborty |
| author_sort | Reza Bayat Mokhtari |
| collection | DOAJ |
| description | Abstract Despite epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), how it senses extracellular matrix (ECM) rigidity remain elusive in the context of the increasing role of tissue rigidity on various hallmarks of cancer development. Here it is shown that EGFR dictates tumorigenic agrin expression in lung cancer cell lines, genetically engineered EGFR‐driven mouse models, and human specimens. Agrin expression confers substrate stiffness‐dependent oncogenic attributes to EGFR‐reliant cancer cells. Mechanistically, agrin mechanoactivates EGFR through epidermal growth factor (EGF)‐dependent and independent modes, thereby sensitizing its activity toward localized cancer cell‐ECM adherence and bulk rigidity by fostering interactions with integrin β1. Notably, a feed‐forward loop linking agrin–EGFR rigidity response to YAP–TEAD mechanosensing is essential for tumorigenesis. Together, the combined inhibition of EGFR–YAP/TEAD may offer a strategy to reduce lung tumorigenesis by disrupting agrin‐EGFR mechanotransduction, uncovering a therapeutic vulnerability for EGFR‐addicted lung cancers. |
| format | Article |
| id | doaj-art-aff06d37e4704fef8b23bbe745446fac |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-aff06d37e4704fef8b23bbe745446fac2025-08-20T03:20:10ZengWileyAdvanced Science2198-38442025-05-011220n/an/a10.1002/advs.202413443An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR‐Addicted Lung TumorigenesisReza Bayat Mokhtari0Divyaleka Sampath1Paige Eversole2Melissa Ong Yu Lin3Dmitriy A. Bosykh4Gandhi T.K. Boopathy5Aravind Sivakumar6Cheng‐Chun Wang7Ramesh Kumar8Joe Yeong Poh Sheng9Ellen Karasik10Barbara A. Foster11Han Yu12Xiang Ling13Wenjie Wu14Fengzhi Li15Zoë Weaver Ohler16Christine F. Brainson17David W. Goodrich18Wanjin Hong19Sayan Chakraborty20Department of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center 265 Elm and Carlton Streets Buffalo NY 14263 USAInstitute of Molecular and Cell Biology 61 Biopolis Drive Proteos Singapore 138673 SingaporeDepartment of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center 265 Elm and Carlton Streets Buffalo NY 14263 USAInstitute of Molecular and Cell Biology 61 Biopolis Drive Proteos Singapore 138673 SingaporeDepartment of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center 265 Elm and Carlton Streets Buffalo NY 14263 USAInstitute of Molecular and Cell Biology 61 Biopolis Drive Proteos Singapore 138673 SingaporeInstitute of Molecular and Cell Biology 61 Biopolis Drive Proteos Singapore 138673 SingaporeInstitute of Molecular and Cell Biology 61 Biopolis Drive Proteos Singapore 138673 SingaporeInstitute of Molecular and Cell Biology 61 Biopolis Drive Proteos Singapore 138673 SingaporeInstitute of Molecular and Cell Biology 61 Biopolis Drive Proteos Singapore 138673 SingaporeDepartment of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center 265 Elm and Carlton Streets Buffalo NY 14263 USADepartment of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center 265 Elm and Carlton Streets Buffalo NY 14263 USADepartment of Biostatistics Roswell Park Comprehensive Cancer Center Buffalo NY 14263 USADepartment of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center 265 Elm and Carlton Streets Buffalo NY 14263 USADepartment of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center 265 Elm and Carlton Streets Buffalo NY 14263 USADepartment of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center 265 Elm and Carlton Streets Buffalo NY 14263 USACenter for Advanced Preclinical Research Frederick National Laboratory for Cancer Research National Cancer Institute NIH Bethesda MD 20892‐1088 USADepartment of Toxicology and Cancer Biology Markey Cancer Center University of Kentucky Lexington KY 40536 USADepartment of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center 265 Elm and Carlton Streets Buffalo NY 14263 USAInstitute of Molecular and Cell Biology 61 Biopolis Drive Proteos Singapore 138673 SingaporeDepartment of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center 265 Elm and Carlton Streets Buffalo NY 14263 USAAbstract Despite epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), how it senses extracellular matrix (ECM) rigidity remain elusive in the context of the increasing role of tissue rigidity on various hallmarks of cancer development. Here it is shown that EGFR dictates tumorigenic agrin expression in lung cancer cell lines, genetically engineered EGFR‐driven mouse models, and human specimens. Agrin expression confers substrate stiffness‐dependent oncogenic attributes to EGFR‐reliant cancer cells. Mechanistically, agrin mechanoactivates EGFR through epidermal growth factor (EGF)‐dependent and independent modes, thereby sensitizing its activity toward localized cancer cell‐ECM adherence and bulk rigidity by fostering interactions with integrin β1. Notably, a feed‐forward loop linking agrin–EGFR rigidity response to YAP–TEAD mechanosensing is essential for tumorigenesis. Together, the combined inhibition of EGFR–YAP/TEAD may offer a strategy to reduce lung tumorigenesis by disrupting agrin‐EGFR mechanotransduction, uncovering a therapeutic vulnerability for EGFR‐addicted lung cancers.https://doi.org/10.1002/advs.202413443agrinEGFR, extracellular matrixhippo pathwaylung cancerYAP/TAZ |
| spellingShingle | Reza Bayat Mokhtari Divyaleka Sampath Paige Eversole Melissa Ong Yu Lin Dmitriy A. Bosykh Gandhi T.K. Boopathy Aravind Sivakumar Cheng‐Chun Wang Ramesh Kumar Joe Yeong Poh Sheng Ellen Karasik Barbara A. Foster Han Yu Xiang Ling Wenjie Wu Fengzhi Li Zoë Weaver Ohler Christine F. Brainson David W. Goodrich Wanjin Hong Sayan Chakraborty An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR‐Addicted Lung Tumorigenesis Advanced Science agrin EGFR, extracellular matrix hippo pathway lung cancer YAP/TAZ |
| title | An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR‐Addicted Lung Tumorigenesis |
| title_full | An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR‐Addicted Lung Tumorigenesis |
| title_fullStr | An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR‐Addicted Lung Tumorigenesis |
| title_full_unstemmed | An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR‐Addicted Lung Tumorigenesis |
| title_short | An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR‐Addicted Lung Tumorigenesis |
| title_sort | agrin yap taz rigidity sensing module drives egfr addicted lung tumorigenesis |
| topic | agrin EGFR, extracellular matrix hippo pathway lung cancer YAP/TAZ |
| url | https://doi.org/10.1002/advs.202413443 |
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