title: ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis.
abstract: The transmembrane metalloprotease-disintegrin ADAM8 mediates cell adhesion and shedding of ligands, receptors and extracellular matrix components. Here, we report that ADAM8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue, especially in triple-negative breast cancers (TNBCs). Furthermore, high ADAM8 levels predicted poor patient outcome. Consistently, ADAM8 promoted an aggressive phenotype of TNBC cells in culture. In a mouse orthotopic model, tumors derived from TNBC cells with ADAM8 knockdown failed to grow beyond a palpable size and displayed poor vascularization. Circulating tumor cells and brain metastases were also significantly reduced. Mechanistically, ADAM8 stimulated both angiogenesis through release of VEGF-A and transendothelial cell migration via β1-integrin activation. In vivo, treatment with an anti-ADAM8 antibody from the time of cell inoculation reduced primary tumor burden and metastases. Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model. As a non-essential protein under physiological conditions, ADAM8 represents a promising novel target for treatment of TNBCs, which currently lack targeted therapies and frequently progress with fatal dissemination.
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Romagnoli
authors.forename: Nora D
authors.initials: ND
authors.lastname: Mineva
authors.forename: Michael
authors.initials: M
authors.lastname: Polmear
authors.forename: Catharina
authors.initials: C
authors.lastname: Conrad
authors.forename: Srimathi
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Delphine
authors.initials: D
authors.lastname: Loussouarn
authors.forename: Sophie
authors.initials: S
authors.lastname: Barillé-Nion
authors.forename: Irene
authors.initials: I
authors.lastname: Georgakoudi
authors.forename: Áine
authors.initials: Á
authors.lastname: Dagg
authors.forename: Enda W
authors.initials: EW
authors.lastname: McDermott
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duffy
authors.forename: Patricia M
authors.initials: PM
authors.lastname: McGowan
authors.forename: Uwe
authors.initials: U
authors.lastname: Schlomann
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.forename: Jörg W
authors.initials: JW
authors.lastname: Bartsch
authors.forename: Gail E
authors.initials: GE
authors.lastname: Sonenshein
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D017434:Protein Structure, Tertiary; D064726:Triple Negative Breast Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D019012:Integrin beta1; D008565:Membrane Proteins; D051722:ADAM Proteins; C068490:ADAM8 protein, human