Publication Date

2018

Journal or Book Title

Biomaterials

Abstract

Cells sense and respond to mechanical cues from the extracellular matrix (ECM) via integrins. ECM stiffness is known to enhance integrin clustering and response to epidermal growth factor (EGF), but we lack information on when or if these mechanosensitive growth factor receptors and integrins converge intracellularly. Towards closing this knowledge gap, we combined a biomaterial platform with transcriptomics, molecular biology, and functional assays to link integrin-mediated mechanosensing and epidermal growth factor receptor (EGFR) signaling. We found that high integrin α6 expression controlled breast cancer cell adhesion and motility on soft, laminin-coated substrates, and this mimicked the response of cells to EGF stimulation. The mechanisms that drove both mechanosensitive cell adhesion and motility converged on calpain 2, an intracellular protease important for talin cleavage and focal adhesion turnover. EGF stimulation enhanced adhesion and motility on soft substrates, but required integrin α6 and calpain 2 signaling. In sum, we identified a new role for integrin α6 mechanosensing in breast cancer, wherein cell adhesion to laminin on soft substrates mimicked EGF stimulation. We identified calpain 2, downstream of both integrin α6 engagement and EGFR phosphorylation, as a common intracellular signaling node, and implicate integrin α6 and calpain 2 as potential targets to inhibit the migration of cancer cells in stiff tumor environments.

License

UMass Amherst Open Access Policy

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Additional Files
References.docx (21 kB)
References
Figure1.pdf (28487 kB)
Figure 1
Figure2.pdf (13227 kB)
Figure 2
Figure3.pdf (972 kB)
Figure 3
Figure 4.pdf (1496 kB)
Figure 4
a6-Supplimental_rev.docx (12213 kB)
Supplementary Materials
Download

Additional files available below

Share

COinS