American Association for Cancer Research
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Supplemental Figure 5 from Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate

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journal contribution
posted on 2023-03-30, 22:47 authored by Matthew G. Rubashkin, Luke Cassereau, Russell Bainer, Christopher C. DuFort, Yoshihiro Yui, Guanqing Ou, Matthew J. Paszek, Michael W. Davidson, Yunn-Yi Chen, Valerie M. Weaver

Vinculin is localized to cell-ECM borders in invasive breast cancer and adhesome proteins are upregulated across human cancers.



Extracellular matrix (ECM) stiffness induces focal adhesion assembly to drive malignant transformation and tumor metastasis. Nevertheless, how force alters focal adhesions to promote tumor progression remains unclear. Here, we explored the role of the focal adhesion protein vinculin, a force-activated mechanotransducer, in mammary epithelial tissue transformation and invasion. We found that ECM stiffness stabilizes the assembly of a vinculin–talin–actin scaffolding complex that facilitates PI3K-mediated phosphatidylinositol (3,4,5)-triphosphate phosphorylation. Using defined two- and three-dimensional matrices, a mouse model of mammary tumorigenesis with vinculin mutants, and a novel super resolution imaging approach, we established that ECM stiffness, per se, promotes the malignant progression of a mammary epithelium by activating and stabilizing vinculin and enhancing Akt signaling at focal adhesions. Our studies also revealed that vinculin strongly colocalizes with activated Akt at the invasive border of human breast tumors, where the ECM is stiffest, and we detected elevated mechanosignaling. Thus, ECM stiffness could induce tumor progression by promoting the assembly of signaling scaffolds, a conclusion underscored by the significant association we observed between highly expressed focal adhesion plaque proteins and malignant transformation across multiple types of solid cancer.See all articles in this Cancer Research section, “Physics in Cancer Research.”Cancer Res; 74(17); 4597–611. ©2014 AACR.