Format

Send to

Choose Destination
Cancer Res. 2014 Sep 1;74(17):4597-611. doi: 10.1158/0008-5472.CAN-13-3698.

Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate.

Author information

1
Center for Bioengineering and Tissue Regeneration, Department of Surgery, UCSF, San Francisco, California.
2
Center for Bioengineering and Tissue Regeneration, Department of Surgery, UCSF, San Francisco, California. Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, New York.
3
National High Magnetic Field Laboratory and Department of Biological Science, Florida State University, Tallahassee, Florida.
4
Department of Pathology, UCSF, San Francisco, California.
5
Center for Bioengineering and Tissue Regeneration, Department of Surgery, UCSF, San Francisco, California. Department of Pathology, UCSF, San Francisco, California. Departments of Anatomy and Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and UCSF Helen Diller Comprehensive Cancer Center, UCSF, San Francisco, California. valerie.weaver@ucsfmedctr.org.

Abstract

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."

PMID:
25183785
PMCID:
PMC4191931
DOI:
10.1158/0008-5472.CAN-13-3698
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center