title: Kaposi sarcoma herpesvirus promotes endothelial-to-mesenchymal transition through Notch-dependent signaling.
abstract: Endothelial-to-mesenchymal transition (EndMT) is now widely considered a pivotal contributor to cancer progression. In this study, we show that the Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a sufficient cause of EndMT, potentially helping to explain the aggressiveness of KS that occurs commonly in AIDS patients. Upon KSHV infection, primary dermal microvascular endothelial cells lost expression of endothelial markers and acquired expression of mesenchymal markers, displaying new invasive and migratory properties along with increased survival. KSHV activated Notch-induced transcription factors Slug and ZEB1, and canonical Notch signaling was required for KSHV-induced EndMT. In contrast, KSHV did not utilize the TGFβ signaling pathway, which has also been linked to EndMT. Within KS lesions, KSHV-infected spindle cells displayed features compatible with KSHV-induced EndMT including a complex phenotype of endothelial and mesenchymal properties, Notch activity, and nuclear ZEB1 expression. Our results show that KSHV engages the EndMT program to increase the invasiveness and survival of infected endothelial cells, traits that likely contribute to viral persistence and malignant progression. One important implication of our findings is that therapeutic approaches to disrupt the Notch pathway may offer novel approaches for KS treatment.
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Gasperini
authors.forename: Georgina
authors.initials: G
authors.lastname: Espigol-Frigole
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McCormick
authors.forename: Ombretta
authors.initials: O
authors.lastname: Salvucci
authors.forename: Dragan
authors.initials: D
authors.lastname: Maric
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Uldrick
authors.forename: Mark N
authors.initials: MN
authors.lastname: Polizzotto
authors.forename: Robert
authors.initials: R
authors.lastname: Yarchoan
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosato
mesh_terms: D002470:Cell Survival; D058750:Epithelial-Mesenchymal Transition; D019288:Herpesvirus 8, Human / Q000472:pathogenicity*; D006801:Humans; D009361:Neoplasm Invasiveness; D051880:Receptors, Notch / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000473:pathology* / Q000821:virology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D051880:Receptors, Notch; D016212:Transforming Growth Factor beta