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. 2011 Dec 15;10(6):577-90.
doi: 10.1016/j.chom.2011.10.011.

KSHV-initiated notch activation leads to membrane-type-1 matrix metalloproteinase-dependent lymphatic endothelial-to-mesenchymal transition

Fang Cheng  1 , Pirita Pekkonen, Simonas Laurinavicius, Nami Sugiyama, Stephen Henderson, Thomas Günther, Ville Rantanen, Elisa Kaivanto, Mervi Aavikko, Grzegorz Sarek, Sampsa Hautaniemi, Peter Biberfeld, Lauri Aaltonen, Adam Grundhoff, Chris Boshoff, Kari Alitalo, Kaisa Lehti, Päivi M Ojala
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Free article

KSHV-initiated notch activation leads to membrane-type-1 matrix metalloproteinase-dependent lymphatic endothelial-to-mesenchymal transition

Fang Cheng et al. Cell Host Microbe. .
Free article

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.

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