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

Area of Science:

• Oncology
• Molecular Biology
• Biophysics

Background:

• Epidermal growth factor receptor (EGFR) is a key oncogene in lung adenocarcinoma (LUAD).
• The role of extracellular matrix (ECM) rigidity in cancer development is increasingly recognized.
• Mechanisms by which EGFR senses ECM rigidity are not well understood.

Purpose of the Study:

• To investigate how EGFR senses ECM rigidity in lung cancer.
• To elucidate the role of agrin in EGFR-mediated mechanotransduction.
• To identify potential therapeutic strategies targeting the EGFR-ECM interaction in LUAD.

Main Methods:

• Analysis of EGFR-driven lung cancer cell lines, genetically engineered mouse models, and human specimens.
• Investigation of agrin expression and its functional role in EGFR-reliant cancer cells.
• Mechanistic studies on agrin-mediated EGFR activation and its interaction with integrin β1.
• Exploration of the interplay between EGFR-agrin signaling and YAP-TEAD mechanosensing.

Main Results:

• EGFR dictates tumorigenic agrin expression in lung cancer.
• Agrin confers substrate stiffness-dependent oncogenic properties to EGFR-reliant cancer cells.
• Agrin mechanoactivates EGFR via EGF-dependent and independent pathways, interacting with integrin β1.
• A feed-forward loop between agrin-EGFR and YAP-TEAD is crucial for tumorigenesis.

Conclusions:

• EGFR senses ECM rigidity through agrin-mediated mechanotransduction.
• The agrin-EGFR-YAP/TEAD axis represents a critical pathway in EGFR-driven lung tumorigenesis.
• Combined inhibition of EGFR and YAP/TEAD may be a viable therapeutic strategy for lung cancers addicted to EGFR.