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

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.卡波西肉瘤（Kaposi’s sarcoma, KS）是一类由卡波西肉瘤相关疱疹病毒（KS-associated herpesvirus, KSHV）引发的艾滋病指征性癌症。目前关于KS仍存在两个尚未明确的科学问题：其细胞谱系起源以及利于病毒致癌发生的条件。本研究鉴定出骨髓来源的血小板衍生生长因子受体α阳性/干细胞抗原1阳性间充质干细胞（Pα(+)S MSCs）为KS梭形细胞祖细胞，并发现KS典型的促血管生成微环境对于KSHV诱导的肉瘤发生至关重要。究其机制，在类KS微环境中培养可使KSHV的表观基因组去抑制，从而使受感染的Pα(+)S MSCs能够表达致癌性KSHV基因。此外，该培养条件可通过PDGFRA信号通路机制，使受KSHV感染的Pα(+)S MSCs克服KSHV介导的癌基因诱导性衰老与细胞周期阻滞；由此证实PDGFRA不仅是KS祖细胞的表型决定因子，同时也是病毒致癌过程的关键介导因子。