title: Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix.
abstract: Metastasis requires tumor cells to navigate through a stiff stroma and squeeze through confined microenvironments. Whether tumors exploit unique biophysical properties to metastasize remains unclear. Data show that invading mammary tumor cells, when cultured in a stiffened three-dimensional extracellular matrix that recapitulates the primary tumor stroma, adopt a basal-like phenotype. Metastatic tumor cells and basal-like tumor cells exert higher integrin-mediated traction forces at the bulk and molecular levels, consistent with a motor-clutch model in which motors and clutches are both increased. Basal-like nonmalignant mammary epithelial cells also display an altered integrin adhesion molecular organization at the nanoscale and recruit a suite of paxillin-associated proteins implicated in invasion and metastasis. Phosphorylation of paxillin by Src family kinases, which regulates adhesion turnover, is similarly enhanced in the metastatic and basal-like tumor cells, fostered by a stiff matrix, and critical for tumor cell invasion in our assays. Bioinformatics reveals an unappreciated relationship between Src kinases, paxillin, and survival of breast cancer patients. Thus adoption of the basal-like adhesion phenotype may favor the recruitment of molecules that facilitate tumor metastasis to integrin-based adhesions. Analysis of the physical properties of tumor cells and integrin adhesion composition in biopsies may be predictive of patient outcome.
authors.affiliation: Department of Chemical Engineering, Stanford University, Stanford, CA 94305.
authors.forename: Armen H
authors.initials: AH
authors.lastname: Mekhdjian
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: FuiBoon
authors.initials: F
authors.lastname: Kai
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Rubashkin
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Louis S
authors.initials: LS
authors.lastname: Prahl
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Laralynne M
authors.initials: LM
authors.lastname: Przybyla
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: McGregor
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Bell
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Barnes
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: DuFort
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Guanqing
authors.initials: G
authors.lastname: Ou
authors.affiliation: Department of Chemical Engineering, Stanford University, Stanford, CA 94305.
authors.forename: Alice C
authors.initials: AC
authors.lastname: Chang
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Luke
authors.initials: L
authors.lastname: Cassereau
authors.affiliation: Department of Chemical Engineering, Stanford University, Stanford, CA 94305.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Tan
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pickup
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Lakins
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
authors.affiliation: National High Magnetic Field Laboratory and Department of Biological Science, Florida State University, Tallahassee, FL 32306.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Davidson
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853.
authors.forename: Jan
authors.initials: J
authors.lastname: Lammerding
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455.
authors.forename: David J
authors.initials: DJ
authors.lastname: Odde
authors.affiliation: Department of Chemical Engineering, Stanford University, Stanford, CA 94305 Valerie.Weaver@ucsf.edu alex.dunn@stanford.edu.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Dunn
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143 Valerie.Weaver@ucsf.edu alex.dunn@stanford.edu.|Departments of Anatomy, Bioengineering and Therapeutic Sciences, and Radiation Oncology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
mesh_terms: D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000503:physiopathology; D051419:Paxillin / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D016023:Integrins; D051419:Paxillin; D051416:Focal Adhesion Protein-Tyrosine Kinases