Project 2: KSHV induces tumorigenesis by harnessing differentiation in hypoxia

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Summary Hypoxia is a characteristic feature of solid tumors and an adverse prognostic factor owing to its contributions to tumor progression and resistance to therapy. Kaposi's sarcoma (KS) preferentially develops in the lower extremities of the body, where blood vessels are often poorly oxygenated, suggesting that hypoxia also plays roles in KS development. Indeed, KSHV infection of endothelial cells or mesenchymal stem cells (MSCs) activates hypoxia-induced factor (HIF), a master regulator of both developmental and pathological angiogenesis. In turn, hypoxia and HIFs affect KSHV biology and KS development. However, given the highly vascular phenotype of KS tumor, we wonder that the hypoxia response may not be the consequence of hypoxia condition, but a strategy that KSHV adapts to promote MSC differentiation towards KS phenotypes. KS lesions are characterized by proliferating KSHV-infected spindle cells, intensive angiogenesis and infiltrating inflammatory cells. The origin of KS spindle cells remains contentious. Recently we found a series of evidence suggesting that KS derives from oral mesenchymal stem cells (MSCs) through a mesenchymal-to- endothelial transition (MEndT) process (Li et al., 2018). These findings revealed novel viral tumorigenesis that cancer can arise from pluripotential stem cells when an oncogenic virus hijacks their differentiation process. Inspired by the exciting discovery, we attempt to elucidate the mechanism underlying KSHV-driven MEndT and tumorigenesis. Our preliminary study showed that the transcriptomes of KSHV infected MSCs and KS lesions largely overlap with that of hypoxia cultured MSCs, raising a possibility that KSHV infection harnesses hypoxia response to promote MSC differentiation leading to KS. We will investigate this hypothesis with three specific aims as follows. (i) We will determine how KSHV promotes MSC differentiation through the hijacking hypoxia response system. (ii) We will identify signaling pathways altered by KSHV and hypoxia and investigate their contribution to MEndT, angiogenesis and inflammation, therefore elucidating the mechanism underlying KSHV and hypoxia-mediated MEndT. (iii) We will characterize epigenetic regulation in MSCs during MEndT, and reveal how KSHV alters the regulation leading to KS. Through these studies, we will ultimately address the question of how KSHV transforms MSC to KS tumor. Our proposed studies are highly innovative and of biological significance. First, the study will prove a paradigm-shifting concept on the nature and cellular origin of Kaposi's sarcoma that KS spindle cells derive from KSHV-infected mesenchymal stem cells. Second, the study will reveal a novel mechanism underlying the emergence of KS tumor cells through KSHV-driven MEndT and new insights into the multifocal and oligoclonal nature of KS. Third, this study will elucidate how KSHV harnesses hypoxia response to promote MSC transformation to KS and validate hypoxia as an effective therapeutic target for the treatment of KS.