KSHV tumorigenesis occurs by environmentally-induced epigenetic adaptation to viral oncogenic gene expression and signaling in pdgfra+ve mesenchymal cancer stem cells

JULIÁN NAIPAUER; LUCAS CAVALLIN; SANTAS ROSARIO; MARTIN ABBA; ENRIQUE A. MESRI

Miami

Simposio; 51st Miami Winter Symposium; 2018

Kaposi's sarcoma (KS), an AIDS-defining cancer caused by the KS herpesvirus (KSHV), is a vascular sarcoma characterized by angiogenesis and spindle-cell proliferation. 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 expression is a main characteristic of mesenchymal stem cells (MSCs), we tested the infection of PDGFRA+ve and PDGFRA-ve MSCs. We found KSHV and PDGFRA co-regulation with robust upregulation of the KSHV oncogenic lytic program leading to tumorigenicity; only when MSCs were grown in Endothelial Progenitor Cell differentiation media (EPC-media). RNAseq analysis showed that KSHV-infected MSCs in EPC-media display a de-repressed KSHV epigenome that allows for expression of oncogenic KSHV lytic genes and PDGFRA activation, in a context of massive downregulation of Histones and a PI3K-AKT signaling signature. 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 that are not tumorigenic massively-upregulated KSHV lytic genes, stopped proliferating and showed senescence features, such as SA-βgal staining. In contrast, KSHV-infected MSCs in EPC media that are tumorigenic, didn?t 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, in the context of PDGFRA and AKT activation. Our data show that tumorigenic KSHV-infected MSCs cells grown in EPC media are epigenetically adapted to overcome KSHV lytic oncogene induction that drives PDGFRA and AKT oncogenic signaling. This work identifies PDGFRA+ve mesenchymal stem cells as potential KS cellular progenitors, in which infection with KSHV is oncogenic only when these cancer stem cells grow in an angiogenic environment generating an epigenome permissive for a derepressed lytic-KSHV oncogenome driving tumorigenesis.