PDGFRA defines the mesenchymal stem cell Kaposi’s sarcoma progenitors by enabling KSHV oncogenesis in an angiogenic environment

NAIPAUER, JULIAN; ROSARIO, SANTAS; GUPTA, SACHIN; PREMER, COURTNEY; MÉNDEZ-SOLÍS, OMAYRA; SCHLESINGER, MARIANA; PONZINIBBIO, VIRGINIA; JAIN, VAIBHAV; GAY, LAUREN; RENNE, ROLF; CHAN, HO LAM; MOREY, LLUIS; SALYAKINA, DARIA; ABBA, MARTIN; WILLIAMS, SION; HARE, JOSHUA M.; GOLDSCHMIDT-CLERMONT, PASCAL J.; MESRI, ENRIQUE A.

PLOS Pathogens

PLOS Pathogens

Año: 2019 vol. 15

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 (Pα(+)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 Pα(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected Pα(+)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.