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

• Published in: PLoS pathogens Vol. 15; no. 12; p. e1008221
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2019; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Angiogenesis; Animals; Biology; Biology and Life Sciences; Bone marrow; Cancer; Carcinogenesis - metabolism; Cell cycle; Consortia; Environmental conditions; Funding; Gene expression; Gene Expression - physiology; Growth conditions; Growth factors; Herpesvirus 8, Human - genetics; HIV; Human immunodeficiency virus; Immunology; Infections; Interdisciplinary aspects; Kaposis sarcoma; Kinases; Medicine and Health Sciences; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - virology; Mesenchyme; Mice; Neovascularization, Pathologic - virology; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Research and Analysis Methods; Sarcoma; Sarcoma, Kaposi - virology; Senescence; Signal Transduction - physiology; Smooth muscle; Stem cells; Supervision; Tumorigenesis; Florida; United States > US; Argentina
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1008221

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.