title: MMP16 Mediates a Proteolytic Switch to Promote Cell-Cell Adhesion, Collagen Alignment, and Lymphatic Invasion in Melanoma.
abstract: Lymphatic invasion and accumulation of continuous collagen bundles around tumor cells are associated with poor melanoma prognosis, but the underlying mechanisms and molecular determinants have remained unclear. We show here that a copy-number gain or overexpression of the membrane-type matrix metalloproteinase MMP16 (MT3-MMP) is associated with poor clinical outcome, collagen bundle assembly around tumor cell nests, and lymphatic invasion. In cultured WM852 melanoma cells derived from human melanoma metastasis, silencing of MMP16 resulted in cell-surface accumulation of the MMP16 substrate MMP14 (MT1-MMP) as well as L1CAM cell adhesion molecule, identified here as a novel MMP16 substrate. When limiting the activities of these trans-membrane protein substrates toward pericellular collagen degradation, cell junction disassembly, and blood endothelial transmigration, MMP16 supported nodular-type growth of adhesive collagen-surrounded melanoma cell nests, coincidentally steering cell collectives into lymphatic vessels. These results uncover a novel mechanism in melanoma pathogenesis, whereby restricted collagen infiltration and limited mesenchymal invasion are unexpectedly associated with the properties of the most aggressive tumors, revealing MMP16 as a putative indicator of adverse melanoma prognosis.
authors: Research Programs Unit, Genome-Scale Biology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Translational Cancer Biology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Olga
authors: O
authors: Tatti
authors: Research Programs Unit, Genome-Scale Biology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Erika
authors: E
authors: Gucciardo
authors: Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors: Pirita
authors: P
authors: Pekkonen
authors: Translational Cancer Biology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Tanja
authors: T
authors: Holopainen
authors: Research Programs Unit, Genome-Scale Biology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Riku
authors: R
authors: Louhimo
authors: Research Programs Unit, Genome-Scale Biology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Pauliina
authors: P
authors: Repo
authors: Skin and Allergy Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Pilvi
authors: P
authors: Maliniemi
authors: Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Jouko
authors: J
authors: Lohi
authors: Research Programs Unit, Genome-Scale Biology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Ville
authors: V
authors: Rantanen
authors: Research Programs Unit, Genome-Scale Biology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Sampsa
authors: S
authors: Hautaniemi
authors: Translational Cancer Biology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Kari
authors: K
authors: Alitalo
authors: Skin and Allergy Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Annamari
authors: A
authors: Ranki
authors: Institute of Biotechnology, University of Helsinki, Helsinki, Finland. Finnish Cancer Institute, Helsinki, Finland.
authors: Päivi M
authors: PM
authors: Ojala
authors: Translational Cancer Biology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Jorma
authors: J
authors: Keski-Oja
authors: Research Programs Unit, Genome-Scale Biology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Finnish Cancer Institute, Helsinki, Finland. kaisa.lehti@helsinki.fi.
authors: Kaisa
authors: K
authors: Lehti
mesh_terms: D000818:Animals; D019556:COS Cells; D002448:Cell Adhesion; D002522:Chlorocebus aethiops; D003094:Collagen / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000473:pathology; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D053513:Matrix Metalloproteinase 16 / Q000502:physiology*; D008545:Melanoma / Q000201:enzymology* / Q000401:mortality / Q000556:secondary; D000090023:Metallothionein 3; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D059748:Proteolysis; D012878:Skin Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology
chemical_list: C507102:MMP16 protein, human; D000090023:Metallothionein 3; C000715430:Mt3 protein, mouse; D039842:Neural Cell Adhesion Molecule L1; D003094:Collagen; D053513:Matrix Metalloproteinase 16; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14