title: MT1-MMP Activation of TGF-β Signaling Enables Intercellular Activation of an Epithelial-mesenchymal Transition Program in Cancer.
abstract: Membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) is associated with cancer invasion and metastasis leading to poor patient prognosis. MT1-MMP mediates cancer cell invasion via degradation of basement membrane and extracellular matrix, and induction of cell migration. However, MT1-MMP expression in the cancer stroma can drive invasion of carcinoma cells in vivo, suggesting MT1-MMP may also promote cancer invasiveness via paracrinemediated mechanisms. A major step in cancer cell metastasis is thought to be an epithelial-mesenchymal transition (EMT), in which carcinoma cells evolve from a stationary epithelial phenotype to a more motile mesenchymal phenotype. We demonstrate here that EMT is triggered by MT1-MMP-mediated activation of TGF-. signaling, involving induction of CUTL1 and subsequently, of Wnt5a. Mesenchymal-like cancer cells expressing endogenous MT1-MMP reverted to an epithelial phenotype when MT1-MMP, SMAD4, CUTL1, or Wnt5a expression or TGF-. activity was inhibited. Wnt5a knockdown in MT1- MMP expressing LNCaP cells caused decreased cell migration and cell growth in soft agar. While MT1-MMP expression did not affect total TGF-. level, MT1-MMP catalytic activity increased the availability of active TGF-., enabling MT1-MMP-expressing cells to activate the EMT in nearby cells. MT1-MMP-expressing cells induced co-cultured non-MT1-MMP-expressing cells to undergo EMT by a TGF-.-dependent process. These results highlight a pathway by which tumor invasiveness may be expanded via MT1-MMP-mediated activation of TGF-. signaling, enabling autocrine and paracrine-mediated induction of EMT.
authors.forename: Hoang-Lan
authors.initials: HL
authors.lastname: Nguyen
authors.forename: Pournima
authors.initials: P
authors.lastname: Kadam
authors.forename: Alex
authors.initials: A
authors.lastname: Helkin
authors.forename: Kevin
authors.initials: K
authors.lastname: Cao
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.forename: Ghassan J
authors.initials: GJ
authors.lastname: Samara
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Stanley
authors.initials: S
authors.lastname: Zucker
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794. Jian.Cao@stonybrookmedicine.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000071818:Wnt-5a Protein / Q000378:metabolism
chemical_list: C080632:CUX1 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000071818:Wnt-5a Protein; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14