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Matrix Rigidity Controls Epithelial-Mesenchymal Plasticity and Tumor Metastasis via a Mechanoresponsive EPHA2/LYN
Laurent Fattet1, Hae-Yun Jung1, Mike W Matsumoto2
1Department of Pharmacology, University of California, San Diego, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Developmental Cell
|June 24, 2020
Summary
Increased extracellular matrix stiffness drives breast cancer metastasis by activating the EPHA2/LYN/TWIST1 pathway. Inhibiting this mechanotransduction pathway halts tumor invasion and spread.
Area of Science:
- Cell Biology
- Biophysics
- Oncology
Background:
- The extracellular matrix (ECM) provides mechanical cues influencing cellular functions.
- In breast cancer, elevated ECM stiffness is linked to epithelial-to-mesenchymal transition (EMT), invasion, and metastasis.
Purpose of the Study:
- To identify a novel mechanosensitive pathway regulating EMT and metastasis in breast cancer.
- To elucidate the role of ECM stiffness in driving tumor progression.
Main Methods:
- Investigated the EPHA2/LYN protein complex's role in mechanotransduction.
- Utilized genetic and pharmacological inhibition strategies.
- Analyzed human breast cancer samples for pathway activation and ECM characteristics.
Main Results:
- Identified a pathway where high ECM stiffness triggers ligand-independent EPHA2 phosphorylation, activating LYN kinase.
- LYN kinase phosphorylates TWIST1, promoting its nuclear entry and triggering EMT and invasion.
- Inhibition of the EPHA2/LYN/TWIST1 pathway suppressed breast tumor invasion and metastasis in vivo.
- Pathway activation correlated with collagen fiber alignment in human breast cancer samples.
Conclusions:
- Revealed a novel EPHA2/LYN/TWIST1 mechanotransduction pathway driven by ECM stiffness.
- This pathway mediates EMT, invasion, and metastasis in response to the tumor microenvironment.
- Targeting this pathway offers a potential therapeutic strategy for breast cancer.
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