title: MT1-MMP modulates melanoma cell dissemination and metastasis through activation of MMP2 and RAC1.
abstract: Metastatic melanoma remains the deadliest of all skin cancers with a survival rate at five years of less than 15%. MT1-MMP is a membrane-associated matrix metalloproteinase that controls pericellular proteolysis and is an important, invasion-promoting, pro-tumorigenic MMP in cancer. We show that deregulation of MT1-MMP expression happens as early as the transition from nevus to primary melanoma and continues to increase during melanoma progression. Furthermore, MT1-MMP expression is associated with poor melanoma patient outcome, underscoring a pivotal role of MT1-MMP in melanoma pathogenesis. We demonstrate that MT1-MMP is directly required for melanoma cells to metastasize, as cells deprived of MT1-MMP fail to form distant metastasis in an orthotopic mouse melanoma model. We show that MT1-MMP affects cell invasion by activating its target MMP2. Importantly, we demonstrate, for the first time, that activation of MMP2 by MT1-MMP is required to sustain RAC1 activity and promote MT1-MMP-dependent cell motility. These data highlight a novel MT1-MMP/MMP2/RAC1 signaling axis in melanoma that may represent an intriguing molecular target for the treatment of invasive melanoma.
authors.affiliation: Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Khvaramze
authors.initials: K
authors.lastname: Shaverdashvili
authors.forename: Poki
authors.initials: P
authors.lastname: Wong
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.forename: Keman
authors.initials: K
authors.lastname: Zhang
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.forename: Barbara
authors.initials: B
authors.lastname: Bedogni
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology*; D016896:Treatment Outcome; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14; D020830:rac1 GTP-Binding Protein
keywords: MMP2; MT1-MMP; RAC1; invasion; migration