PDGFRA DEFINES A POPULATION OF MESENCHYMAL STEM CELL KAPOSI?S SARCOMA PROGENITORS BY ENABLING ONCOGENESIS IN AN ANGIOGENIC ENVIRONMENT

NAIPAUER J; ROSARIO S; ABBA MC; MESRI EA

Congreso; The Fourth South American Symposium in Signal Transduction and Molecular Medicine; 2018

Kaposi?s sarcoma (KS) is an AIDS-defining cancer caused by Kaposi's sarcoma herpesvirus (KSHV). Pending questions on KS are its cellular ontology and the molecular mechanisms of viral oncogenesis. Since we identified PDGFRA as a predominant oncogenic signaling triggered by KSHV in KS, and PDGFRA is a key phenotypic and functional mesenchymal stem cell (MSC) marker, we tested KSHV infection of PDGFRA+ve and PDGFRA-ve MSCs. We found an upregulation of theKSHV oncogenic lytic program leading to tumorigenicity; only when PDGFRA+ve MSCs were grown in a pro-angiogenic/vasculogenic environment (EPC-media). RNAseq and ChIP-seq analysis showed that KSHV-infected MSCs in EPC-media display a de-repressed KSHV epigenome that allows for expression of oncogenic KSHV lytic genes. We used KSHV lytic induction with an HDAC inhibitor (SAHA/Vorinostat) tomimic KSHV in vivo lytic switch. KSHV-infected MSCs grown in MSC media, which are not tumorigenic massively-upregulated KSHV lytic genes, stopped proliferating and showed senescence features. In contrast, KSHV-infected MSCs in EPC media that are tumorigenic did not further enhanced KSHV lytic gene expression neither displayed senescence features after SAHA treatment. Moreover, these cells continue proliferating even in the presence of p53 and p21 upregulation with concomitant PDGFRA and AKT activation, suggesting that infected MSCs grown in EPC media are epigenetically adapted to overcome KSHV lytic-driven oncogene-induced senescence through PDGFRA signaling activation. Inhibition of PDGFR signaling during KSHV lytic reactivation blocks cell proliferation and induce senescence, validating PDGFRAsignaling as an oncogenesis pathway that sustains infected cell survival and proliferation. Thus, PDGFRA defines a population of MSC Kaposi?s sarcoma progenitors by enabling KSHV oncogenesis in an angiogenic environment.