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.

DOI: 10.1016/j.chom.2011.10.011
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@article{Cheng2011KSHVinitiatedNA, title={KSHV-initiated notch activation leads to membrane-type-1 matrix metalloproteinase-dependent lymphatic endothelial-to-mesenchymal transition.}, author={Fang Cheng and Pirita Pekkonen and Simonas Laurinavicius and Nami Sugiyama and Stephen Henderson and Thomas G{\"{u}nther and Ville Rantanen and Elisa Kaivanto and Mervi Aavikko and Grzegorz Sarek and Sampsa Hautaniemi and Peter Biberfeld and Lauri A. Aaltonen and Adam T Grundhoff and Chris Boshoff and Kari Alitalo and Kaisa I. Lehti and P{\"a}ivi M. Ojala}, journal={Cell host & microbe}, year={2011}, volume={10 6}, pages={577-90} }