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

Author:

Mokhtari, Reza Bayat

Sampath, Divyaleka

Eversole, Paige

Yu Lin, Melissa Ong

Bosykh, Dmitriy A

Boopathy, Gandhi T K

Sivakumar, Aravind

Wang, Cheng-Chun

Kumar, Ramesh

Sheng, Joe Yeong Poh

Karasik, Ellen

Foster, Barbara A

Yu, Han

Ling, Xiang

Wu, Wenjie

Li, Fengzhi

Ohler,Zoe

Brainson, Christine F

Goodrich, David W

Hong, Wanjin

Chakraborty, Sayan [ORCID]
Author Address

Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, 265 Elm and Carlton Streets, Buffalo, NY, 14263, USA., Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore, 138673, Singapore., Department of Biostatistics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA., Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892-1088, USA., Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA., Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA., Program of Developmental Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.,

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 ß1. 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. © 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.

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Author Address