Project 3: Skin hypoxia, MCPyV infection, and MCC tumorigenesis

项目3：皮肤缺氧、MCPyV感染和MCC肿瘤发生

• 批准号: 10714175
• 负责人: Jianxin You
• 金额: $ 41.86万
• 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/10714175
• 关键词: AIDS related cancer; Affect; Automobile Driving; Cancer Etiology; Cell Hypoxia; Cell Proliferation; Cells; ChIP-seq; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Binding; DNA Sequence Alteration; Data; Dermis; Development; Disseminated Malignant Neoplasm; Environment; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Genome; Hair follicle structure; Human; Hypoxia; Immunosuppression; In Vitro; Incidence; Infectious Skin Diseases; Knock-out; Knowledge; Malignant Neoplasms; Mediating; Merkel Cells; Merkel cell carcinoma; Messenger RNA; Metabolic; Modeling; Neoplasm Metastasis; Oncogenes; Oncogenic; Oncogenic Viruses; Organoids; Polyomavirus; Polyomavirus Infections; Proliferating; Reader; Risk Factors; Skin; Skin Cancer; Small Interfering RNA; Subcutaneous Tissue; Testing; Therapeutic Intervention; Transcriptional Regulation; Tumor Promotion; Up-Regulation; VEGFA gene; Vascular Endothelial Growth Factors; Viral; Viral Genome; Viral Oncogene; Virus; Virus Diseases; Virus Integration; Virus Replication; Xenograft Model; angiogenesis; carbonate dehydratase; carcinogenesis; chronic infection; coping; improved; insight; knock-down; laser capture microdissection; lipid nanoparticle; metaplastic cell transformation; mortality; nanoparticle delivery; neoplastic cell; novel strategies; pressure; prevent; recruit; response; transcriptome; tumor; tumor growth; tumor hypoxia; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

Project Abstract Merkel cell carcinoma (MCC) is one of the most aggressive skin cancers. Clonal integration of Merkel cell polyomavirus (MCPyV) genome into the host DNA has been observed in ~80% of MCCs, and represents a key causal factor for MCC development. LT and sT encoded by MCPyV genome have been shown to support not only viral replication but also MCPyV-induced tumorigenesis. Immune suppression is another important risk factor for the development of MCPyV-associated MCC. MCC has a nearly 50% mortality rate. The incidence of MCC has increased by >95% in the US since 2000. MCC is highly prone to metastasis. The metastatic cancers are more difficult to treat and can often be fatal. Thus, there is a need to better understand the oncogenic mechanisms of MCPyV and MCC in order to develop new strategies to prevent and treat this highly lethal skin cancer. MCC tumors are usually detected in the human dermis, which maintain a hypoxic microenvironment. Hypoxia supports tumor progression partly by driving metabolic adaptation, angiogenesis and metastasis, through upregulation of hypoxia-regulated genes. Importantly, we found that a large number of hypoxia genes are highly induced in MCC, suggesting that the hypoxic skin microenvironment represents an important starting point for MCC progression and metastatic spread. Some of these genes such as carbonic anhydrase 9 (CA9) and vascular endothelial growth factor A (VEGF-A) are critical for promoting tumor growth and metastasis. However, how MCPyV infected cells and MCC tumor cells respond to hypoxia and the impact of hypoxia-regulated gene expression on MCPyV infection and MCC tumorigenesis remain largely unknown. We showed that MCPyV oncogene LT is associated with epigenetic reader BRD4, which functionally interacts with HIF-1α, a key regulator of hypoxic responses, to control the transcription of hypoxic genes such as CA9 and VEGF-A. We also found that MCPyV sT can induce hypoxic gene expression. Building on these findings, we hypothesize that collaborative interactions between MCPyV LT and sT with their host partners, such as BRD4 and HIF-1α, collectively regulate hypoxia gene expression in MCPyV-infected and MCC origin cells to promote viral infection and MCC tumorigenesis. In this project, we propose to determine how MCPyV interacts with the host cells in the hypoxic skin environment (Aim 1), characterize the impact of LT-BRD4-HIF-1α interaction on hypoxic gene expression in skin cells (Aim 2), and investigate the function of MCPyV oncogenes in controlling MCC hypoxic reprograming and the impact on MCC tumorigenesis (Aim 3). These results will fill the gap in our understanding of hypoxic response mechanism in MCPyV-infected cells and associated MCC. Our study may provide new insights into viral and cellular factors that support hypoxia-mediated metabolic reprogramming during MCPyV infection and MCC oncogenic development, revealing new strategies to improve therapeutic intervention of MCPyV-induced cancers.

项目摘要 默克尔细胞癌（MCC）是默克尔细胞克隆整合最具侵袭性的皮肤癌之一。 在约 80% 的 MCC 中观察到多瘤病毒 (MCPyV) 基因组进入宿主 DNA，并且代表了关键的 MCPyV 基因组编码的 LT 和 sT 已被证明是 MCC 发展的致病因素。 除了病毒复制之外，MCPyV 诱导的肿瘤发生也是另一个重要风险。 MCPyV 相关 MCC 的发生率接近 50%。 自 2000 年以来，MCC 在美国增加了 >95%。MCC 极易发生转移。 癌症更难治疗，并且往往是致命的，因此，有必要更好地了解癌症。 MCPyV 和 MCC 的致癌机制，以制定新的策略来预防和治疗这种高度 致命的皮肤癌通常在维持缺氧的人类真皮中检测到。 缺氧部分通过促进代谢适应、血管生成来支持肿瘤进展。 重要的是，我们发现，通过上调缺氧调节基因来抑制和转移。 缺氧基因在 MCC 中被高度诱导，表明缺氧的皮肤微环境代表了 其中一些基因（例如碳酸基因）是 MCC 进展和转移扩散的重要起点。 脱水酶 9 (CA9) 和血管内皮生长因子 A (VEGF-A) 对于促进肿瘤生长至关重要 然而，MCPyV感染细胞和MCC肿瘤细胞如何应对缺氧及其影响。 缺氧调节基因表达对 MCPyV 感染和 MCC 肿瘤发生的影响仍然很大程度上未知。 我们发现 MCPyV 癌基因 LT 与表观遗传阅读器 BRD4 相关，后者在功能上相互作用 与缺氧反应的关键调节因子 HIF-1α 一起控制缺氧基因（如 CA9）的转录 基于这些发现，我们还发现 MCPyV sT 可以诱导缺氧基因表达。 我们欢迎 MCPyV LT 和 sT 与其宿主合作伙伴之间的协作互动，例如 BRD4 和 HIF-1α 共同调节 MCPyV 感染和 MCC 起源细胞中的缺氧基因表达 促进病毒感染和 MCC 肿瘤发生 在这个项目中，我们建议确定 MCPyV 如何相互作用。 与缺氧皮肤环境中的宿主细胞（目标 1）一起，表征 LT-BRD4-HIF-1α 的影响 皮肤细胞缺氧基因表达的相互作用（目标2），并研究MCPyV癌基因的功能 控制 MCC 缺氧重编程以及对 MCC 肿瘤发生的影响（目标 3）。 我们对 MCPyV 感染细胞和相关 MCC 缺氧反应机制的理解存在差距。 我们的研究可能为支持缺氧介导的代谢的病毒和细胞因素提供新的见解 MCPyV 感染和 MCC 致癌发展过程中的重编程，揭示了新的策略 改善 MCPyV 诱导的癌症的治疗干预。