KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis

Lucas E. Cavallin, Qi Ma, Julian Naipauer, Sachin Gupta, Mani Kurian, Paola Locatelli, Paolo Romanelli, Mehrdad Nadji, Pascal J. Goldschmidt-Clermont, Enrique A. Mesri

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Kaposi’s sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) KSHV infected spindle cells of most AIDS-KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis. Our data show that KSHV usurps sarcomagenic PDGFRA signaling to drive KS. This and the fact that PDGFRA drives non-viral sarcomas highlights the importance for KSHV-induced ligand-mediated activation of PDGFRA in KS sarcomagenesis and shows that this oncogenic axis could be successfully blocked to impede KS tumor growth.

Original languageEnglish (US)
Article numbere1007175
JournalPLoS pathogens
Volume14
Issue number7
DOIs
StatePublished - Jul 2018

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Cavallin, L. E., Ma, Q., Naipauer, J., Gupta, S., Kurian, M., Locatelli, P., Romanelli, P., Nadji, M., Goldschmidt-Clermont, P. J., & Mesri, E. A. (2018). KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis. PLoS pathogens, 14(7), [e1007175]. https://doi.org/10.1371/journal.ppat.1007175