2. Academic Validation
  3. α5β1-Integrin promotes tension-dependent mammary epithelial cell invasion by engaging the fibronectin synergy site

α5β1-Integrin promotes tension-dependent mammary epithelial cell invasion by engaging the fibronectin synergy site

  • Mol Biol Cell. 2017 Nov 1;28(22):2958-2977. doi: 10.1091/mbc.E17-02-0126.
Y A Miroshnikova 1,  G I Rozenberg 2,  L Cassereau 1,  M Pickup 1,  J K Mouw 1,  G Ou 1,  K L Templeman 3,  E-I Hannachi 3,  K J Gooch 2,  A L Sarang-Sieminski 2,  A J García 3,  V M Weaver 4 5
Affiliations

Affiliations

  • 1 Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, CA 94143.
  • 2 Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104.
  • 3 Woodruff School of Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332.
  • 4 Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, CA 94143 [email protected].
  • 5 Department of Anatomy and Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143.
PMID: 28877984 DOI: 10.1091/mbc.E17-02-0126
Abstract

Tumors are fibrotic and characterized by abundant, remodeled, and cross-linked Collagen that stiffens the extracellular matrix stroma. The stiffened collagenous stroma fosters malignant transformation of the tissue by increasing tumor cell tension to promote focal adhesion formation and potentiate growth factor receptor signaling through kinase. Importantly, Collagen cross-linking requires fibronectin (FN). Fibrotic tumors contain abundant FN, and tumor cells frequently up-regulate the FN receptor α5β1 Integrin. Using transgenic and xenograft models and tunable two- and three-dimensional substrates, we show that FN-bound α5β1 Integrin promotes tension-dependent malignant transformation through engagement of the synergy site that enhances Integrin adhesion force. We determined that ligation of the synergy site of FN permits tumor cells to engage a zyxin-stabilized, vinculin-linked scaffold that facilitates nucleation of phosphatidylinositol (3,4,5)-triphosphate at the plasma membrane to enhance phosphoinositide 3-kinase (PI3K)-dependent tumor cell invasion. The data explain why rigid Collagen fibrils potentiate PI3K activation to promote malignancy and offer a perspective regarding the consistent up-regulation of α5β1 Integrin and FN in many tumors and their correlation with Cancer aggression.

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