PDGFRA Defines the Mesenchymal Stem Cell Kaposi's Sarcoma Progenitors by Enabling KSHV Oncogenesis in an Angiogenic Environment [RNA-seq]

Kaposi's sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (Pa(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected Pa(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected Pa(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis. Overall design: We designed a novel model of “de novo” KSHV oncogenesis based on infection of PDGFRA-positive mesenchymal stem cell progenitors cultured in pro-angiogenic/vasculogenic KS-like growth conditions. This system serves as a unique and robust platform to identify KSHV oncogenic-pathways and their relationship with cellular lineages and extracellular growth environments. Additionally, it can further be exploited to genetically dissect and elucidate viral, host-cell and environmental features of KS pathobiology.