PDGFRA Defines the Mesenchymal Stem Cell Kaposi's Sarcoma Progenitors by Enabling KSHV Oncogenesis in an Angiogenic Environment

NAIPAUER J; ROSARIO S; GUPTA S; PREMER C; MENDEZ-SOLIS O; SCHLESINGER M; PONZINIBBIO V; JAIN V; GAY L; RENNE R; CHAN L; MOREY L; SALYAKINA D; ABBA MC; WILLIAMS S; HARE JM; GOLDSCHMIDT PJ; MESRI EA

PLOS PATHOGENS

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2019

1553-7366

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.