An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR‐Addicted Lung Tumorigenesis

An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR‐Addicted Lung Tumorigenesis

Advanced Science

10.1002/advs.202413443

https://doi.org/10.1002/advs.202413443

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

Cell Biology

01 April 2025

Mokhtari, R. B., Sampath, D., Eversole, P., Yu Lin, M. O., Bosykh, D. A., Boopathy, G. T. K., Sivakumar, A., Wang, C., Kumar, R., Sheng, J. Y. P., Karasik, E., Foster, B. A., Yu, H., Ling, X., Wu, W., Li, F., Ohler, Z. W., Brainson, C. F., Goodrich, D. W., … Chakraborty, S. (2025). An Agrin–YAP/TAZ Rigidity Sensing Module Drives EGFR‐Addicted Lung Tumorigenesis. Advanced Science, 12(20). Portico. https://doi.org/10.1002/advs.202413443

AbstractDespite 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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Research Foundation - Competitive Research Programme
Grant Reference no. : NRF-CRP28-2022-0001

This research is supported by core funding from: A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB)
Grant Reference no. :

https://oar.a-star.edu.sg/communities-collections/articles/22753

2198-3844
2198-3844

Institute of Molecular and Cell Biology

https://doi.org/10.1002/advs.202413443