title: KSHV-initiated notch activation leads to membrane-type-1 matrix metalloproteinase-dependent lymphatic endothelial-to-mesenchymal transition.
abstract: Kaposi sarcoma (KS), an angioproliferative disease associated with Kaposi sarcoma herpesvirus (KSHV) infection, harbors a diversity of cell types ranging from endothelial to mesenchymal cells of unclear origin. We developed a three-dimensional cell model for KSHV infection and used it to demonstrate that KSHV induces transcriptional reprogramming of lymphatic endothelial cells to mesenchymal cells via endothelial-to-mesenchymal transition (EndMT). KSHV-induced EndMT was initiated by the viral proteins vFLIP and vGPCR through Notch pathway activation, leading to gain of membrane-type-1 matrix metalloproteinase (MT1-MMP)-dependent invasive properties and concomitant changes in viral gene expression. Mesenchymal markers and MT1-MMP were found codistributed with a KSHV marker in the same cells from primary KS biopsies. Our data explain the heterogeneity of cell types within KS lesions and suggest that KSHV-induced EndMT may contribute to KS development by giving rise to infected, invasive cells while providing the virus a permissive cellular microenvironment for efficient spread.
authors.affiliation: Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Fang
authors.initials: F
authors.lastname: Cheng
authors.forename: Pirita
authors.initials: P
authors.lastname: Pekkonen
authors.forename: Simonas
authors.initials: S
authors.lastname: Laurinavicius
authors.forename: Nami
authors.initials: N
authors.lastname: Sugiyama
authors.forename: Stephen
authors.initials: S
authors.lastname: Henderson
authors.forename: Thomas
authors.initials: T
authors.lastname: Günther
authors.forename: Ville
authors.initials: V
authors.lastname: Rantanen
authors.forename: Elisa
authors.initials: E
authors.lastname: Kaivanto
authors.forename: Mervi
authors.initials: M
authors.lastname: Aavikko
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Sarek
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: Peter
authors.initials: P
authors.lastname: Biberfeld
authors.forename: Lauri
authors.initials: L
authors.lastname: Aaltonen
authors.forename: Adam
authors.initials: A
authors.lastname: Grundhoff
authors.forename: Chris
authors.initials: C
authors.lastname: Boshoff
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Kaisa
authors.initials: K
authors.lastname: Lehti
authors.forename: Päivi M
authors.initials: PM
authors.lastname: Ojala
mesh_terms: D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology / Q000821:virology; D058750:Epithelial-Mesenchymal Transition; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000201:enzymology / Q000821:virology; D051880:Receptors, Notch / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D015398:Signal Transduction; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051880:Receptors, Notch; D014764:Viral Proteins; D053511:Matrix Metalloproteinase 14