Project 2: KSHV induces tumorigenesis by harnessing differentiation in hypoxia

项目2：KSHV利用缺氧条件下的分化诱导肿瘤发生

• 批准号: 10714174
• 负责人: ERLE S. ROBERTSON
• 金额: $ 45.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714174
• 关键词: AIDS related cancer; Address; Affect; Biological; Biology; Blood Vessels; Cell Differentiation process; Cell Fate Control; Cell Lineage; Cell Reprogramming; Cells; Characteristics; Chromatin; Development; Endothelial Cells; Endothelium; Epigenetic Process; Etiology; Event; Evolution; Exhibits; Gene Expression; Gene set enrichment analysis; Genes; Genetic Transcription; Goals; Health; Herpesviridae Infections; Human; Human Herpesvirus 8; Hypoxia; Inflammation; Inflammatory Infiltrate; Kaposi Sarcoma; Lesion; Literature; Lower Extremity; Macrophage; Malignant Neoplasms; Mediating; Mesenchymal; Mesenchymal Differentiation; Mesenchymal Stem Cells; Modeling; Nature; Oncogenic; Oncogenic Viruses; Ontology; Oral; Pathologic Neovascularization; Pathway interactions; Phenotype; Play; Prevention; Process; Prognostic Factor; Proliferating; Property; Regulation; Reporting; Role; Series; Signal Pathway; Signal Transduction; Skin Tissue; Smooth Muscle; Solid Neoplasm; Spindle Cell Sarcomas; Stimulus; System; Vascular Endothelial Growth Factors; Viral; Virus; adult stem cell; angiogenesis; cell transformation; differential expression; epigenetic regulation; histone modification; innovation; insight; neoplastic cell; novel; programs; response; self-renewal; stem cell differentiation; stem cells; therapeutic target; therapeutically effective; therapy resistant; transcriptome; transcriptome sequencing; tumor; tumor microenvironment; tumor progression; tumorigenesis; vasculogenesis

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.

概括 缺氧是实体瘤的一个特征，也是一个不良预后因素，因为它有助于 肿瘤进展和对治疗的抵抗。卡波西肉瘤 (KS) 优先发展于下颌 身体四肢的血管常常缺氧，这表明缺氧也会影响 KS 开发中的角色。事实上，KSHV 感染内皮细胞或间充质干细胞 (MSC) 激活缺氧诱导因子 (HIF)，这是发育和病理的主要调节因子 血管生成。反过来，缺氧和 HIF 会影响 KSHV 生物学和 KS 发育。然而，鉴于高度 KS 肿瘤的血管表型，我们想知道缺氧反应可能不是以下因素的结果 缺氧条件下，而是 KSHV 采取的促进 MSC 向 KS 表型分化的策略。 KS 病变的特点是感染 KSHV 的梭形细胞增殖、密集的血管生成和 浸润炎症细胞。 KS 梭形细胞的起源仍然存在争议。最近我们发现了一系列 有证据表明 KS 通过间充质转化为口腔间充质干细胞 (MSC) 内皮转化（MEndT）过程（Li et al., 2018）。这些发现揭示了新的病毒肿瘤发生机制 当致癌病毒劫持多能干细胞的分化过程时，就会产生癌症。 受到这一令人兴奋的发现的启发，我们试图阐明 KSHV 驱动的 MEndT 的潜在机制 肿瘤发生。我们的初步研究表明，KSHV 感染的 MSC 和 KS 病变的转录组 与缺氧培养的间充质干细胞很大程度上重叠，这提出了 KSHV 感染利用缺氧的可能性 促进 MSC 分化导致 KS 的反应。我们将用三个具体的方法来研究这个假设 目标如下。 (i) 我们将确定KSHV如何通过劫持缺氧促进MSC分化 响应系统。 (ii) 我们将确定 KSHV 和缺氧改变的信号传导途径并研究它们 对 MEndT、血管生成和炎症的贡献，从而阐明 KSHV 的潜在机制 和缺氧介导的 MEndT。 (iii) 我们将在 MEndT 期间描述 MSC 的表观遗传调控特征，以及 揭示 KSHV 如何改变导致 KS 的调节。通过这些研究，我们最终将解决 KSHV 如何将 MSC 转化为 KS 肿瘤的问题。 我们提出的研究具有高度创新性和生物学意义。首先，该研究将证明 关于 KS 梭形细胞衍生的卡波西肉瘤的性质和细胞起源的范式转换概念 来自 KSHV 感染的间充质干细胞。其次，该研究将揭示潜在的新机制 通过 KSHV 驱动的 MEndT 出现 KS 肿瘤细胞以及对多灶性和寡克隆的新见解 KS 的性质。第三，本研究将阐明 KSHV 如何利用缺氧反应来促进 MSC 转化为 KS 并验证缺氧作为治疗 KS 的有效治疗靶点。