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- Title
PDGFRA defines the mesenchymal stem cell Kaposi's sarcoma progenitors by enabling KSHV oncogenesis in an angiogenic environment.
- 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.
- Abstract
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. Author summary: Identification of the KS progenitor cell creates the possibility of studying viral oncogenesis and its determinants from its initial steps as a continuum. It also increases our understanding of pathogenic mechanisms and disease preferential tropism. Hereby we identify Pα(+)S-MSCs as KS progenitors, in which KSHV infection has oncogenic consequences; only when these cells are in a pro-angiogenic environment in which PDGFRA activation enables an oncogenic de-repressed KSHV epigenome. These results identify a KS-progenitor population in the Pα(+)S-MSCs and point to pro-angiogenic environmental conditions as essential for oncogenic viral gene expression and transformation. We designed a novel model of KSHV oncogenesis, creating a very robust platform to identify KSHV oncogenic pathways and their relationship with cellular lineages and extracellular growth environments.
- Subjects
KAPOSI'S sarcoma; MESENCHYMAL stem cells; NEOPLASTIC cell transformation; CELLULAR aging; VIRAL genes; PROGENITOR cells
- Publication
PLoS Pathogens, 2019, Vol 15, Issue 12, pN.PAG
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1008221