title: Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate.
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."
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, UCSF, San Francisco, California.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Rubashkin
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, UCSF, San Francisco, California.
authors.forename: Luke
authors.initials: L
authors.lastname: Cassereau
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, UCSF, San Francisco, California.
authors.forename: Russell
authors.initials: R
authors.lastname: Bainer
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, UCSF, San Francisco, California.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: DuFort
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, UCSF, San Francisco, California.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yui
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, UCSF, San Francisco, California.
authors.forename: Guanqing
authors.initials: G
authors.lastname: Ou
authors.affiliation: 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.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Paszek
authors.affiliation: National High Magnetic Field Laboratory and Department of Biological Science, Florida State University, Tallahassee, Florida.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Davidson
authors.affiliation: Department of Pathology, UCSF, San Francisco, California.
authors.forename: Yunn-Yi
authors.initials: YY
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D016608:Talin / Q000378:metabolism; D016596:Vinculin / Q000378:metabolism*
chemical_list: D000199:Actins; D018129:Phosphatidylinositol Phosphates; D016608:Talin; C060974:phosphatidylinositol 3,4,5-triphosphate; D016596:Vinculin; D019869:Phosphatidylinositol 3-Kinases