PDGFRA defines a population of mesenchymal stem cell Kaposi?s Sarcoma progenitors by enabling oncogenesis in an angiogenic environment

JULIÁN NAIPAUER; SANTAS ROSARIO; COURTNEY PREMER; SACHIN GUPTA; LUCAS CAVALLIN; VIRGINIA PONZINIBBIO; JAIN VAIBHAV; RENNE ROLF; CHAN HL; MOREY LLUIS; DARIA SALYAKINA; ABBA MARTIN; JOSHUA HARE; PASCAL J GOLDSCHMIDT-CLERMONT; ENRIQUE MESRI

Simposio; Miami Winter Symposium 2019 Evolving Concepts in HIV and Emerging Viral Infections; 2019

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 the KSHV oncogenic lytic program leading to tumorigenicity; only when PDGFRA+ve MSCs were grown in a pro-angiogenic KS-like environment. RNAseq and ChIP-seq analysis showed that KSHV-infected MSCs in KS-like environment 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) to mimic 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 KS-like environment, 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 PDGFRA+ve MSCs grown in KS-like environment 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 PDGFRA signaling 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 a KS-like environment.