Interplay between PDGFRA, oxygen-regulated translation and KSHV in Kaposi's sarcomagenesis

PDGFRA、氧调节翻译和 KSHV 在卡波西肉瘤发生中的相互作用

• 批准号: 10381113
• 负责人: Enrique A Mesri
• 金额: $ 3.86万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381113
• 关键词: AIDS related cancer; Acquired Immunodeficiency Syndrome; Binding; Bypass; Cells; Cellular Stress; Clinical; Complex; Development; Disease; Environment; FRAP1 gene; Genes; Human Herpesvirus 8; Hypoxia; Imatinib; In Vitro; Infection; Kaposi Sarcoma; Knowledge; Lytic; Mediating; Mediator of activation protein; Mesenchymal Stem Cells; Natural Immunity; Oncogenes; Oncogenic; Oxygen; PDGFRA gene; Pathogenesis; Pathway interactions; Phosphotransferases; Platelet-Derived Growth Factor; Process; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-akt; RNA Cap-Binding Proteins; Regulation; Signal Transduction; Stress; System; Therapeutic; Tissues; Translation Initiation; Translations; Viral; Viral Oncogene; Virus; Virus Diseases; Virus Replication; base; in vivo Model; insight; novel therapeutics; paracrine; phenotypic biomarker; progenitor; recruit; targeted treatment; therapeutic target; therapy design; tumorigenesis

In spite of continuous improvements in our understanding of KSHV KS sarcomagenesis and the implementation of rationally designed therapies based on these advances, advanced AIDS-KS is mostly an incurable disease and many of the most promising new therapies continue to have major roadblocks and implementation problems particularly in the setting of ART. Our lab has made major contributions to the elucidation of viral mechanisms of oncogenesis and the host oncogenic mechanisms they elicit and the implementation of potential therapeutic approaches. In the last cycle of this R01:1) We have shown that KSHV lytic genes; and particularly the vGPCR oncogene can induce PDGF-mediated activation of PDGFRA, that PDGFRA is the most prominently activated RTK in AIDS-KS that is an oncogenic driver and a therapeutic target in AIDS-KS which in the Imatinib trials showed clinical prowess. 2) Based on the insight that PDGFRA is a critical oncogenic pathway recruited by the KSHV we reasoned that an oncogenic KS progenitor should be a PDGFRA(+) cell. This led us to the identification of PDGFRA mesenchymal stem cells as KS progenitors and PDGFRA; not only as a phenotypic marker, but also as an enabler of KSHV oncogenesis in an angiogenic KS- like environment. This discovery led to the development of a new KSHV infection-to-tumorigenesis system that allows to dissect the effect of the angiogenic microenvironment and the contribution of viral and host mechanisms to oncogenesis, using in vitro and in vivo models 3) We found that KSHV ability to regulate the oxygen sensing machinery allows the virus to coopt the hypoxia-regulated alternative translation initiation machinery eIF4EH activated by HIF2a and mediated by eIF4E2 cap-binding protein, which we found was essential for KSHV replication, for escaping the viral shut-off and for PDGFRA driven pathogenesis in MSCs. The importance of this discovery is that through its regulation of the oxygen sensing machinery (O2SM) the virus can access to translation initiation plasticity (TRIP), defined as the ability for KSHV to alternatively initiate protein synthesis using both the initiation complex eIF4E bearing a cap-binding regulated by the PI3K-AKT- mTORC1-HIF1a axis (eIF4E1 cap-binding) or the eIF4EH (eIF4E2 cap-binding) regulated by HIF2a. We hypothesize that this confers to KSHV several adaptive advantages that we will study in: Aim 1) It allows the virus to maximize replication in different oxygen levels corresponding to variety of tissues and pathophysiological conditions and It may allow the virus to bypass stress and innate immunity-related kinases (PERK and PKR) targeted eIF2a inhibition 2) It may be employed by viral oncogenes such as vGPCR and/or its host cell signaling mediators such as PDGFRA for proliferation and the induction of direct and paracrine oncogenesis Aim 3) Could allow the transformed host cell to be plastic and adaptive in the context of AIDS-KS therapies targeting PDGFRA such as Imatinib, which are known to target the PDGFRA-AKT-mTOR-E1-HIF1a pathway.

尽管我们对KSHV KS肉瘤的理解有着不断的改善和 基于这些进步的合理设计疗法实施，高级艾滋病 - 主要是 无法治愈的疾病和许多最有前途的新疗法继续具有主要的障碍和 实施问题，尤其是在艺术环境中。我们的实验室为 阐明肿瘤发生的病毒机制和他们引起的宿主癌症机制和 实施潜在的治疗方法。在此R01的最后一个周期中：1）我们已经证明了KSHV 裂解基因；尤其是VGPCR癌基因可以诱导PDGF介导的PDGFRA激活，即 PDGFRA是AIDS-K中最突出的RTK，它是一种致癌驱动力和治疗性的RTK 在伊替尼试验中，艾滋病中的目标显示出临床能力。 2）基于PDGFRA的见解 KSHV招募的关键致癌途径我们认为致癌KS祖细胞应为 PDGFRA（+）单元格。这导致我们鉴定了PDGFRA间充质干细胞为KS祖细胞和 PDGFRA;不仅是表型标记，而且作为血管生成KS-中KSHV肿瘤发生的推动剂 喜欢环境。这一发现导致开发了一种新的KSHV感染到肿瘤性系统，该系统 允许剖析血管生成微环境的作用以及病毒和宿主的贡献 肿瘤发生的机制，使用体外和体内模型3）我们发现KSHV调节能力 氧气传感机械允许病毒加强缺氧调节的替代翻译启动 由HIF2A激活并由EIF4E2盖结合蛋白介导的机械EIF4EH，我们发现这是 对于KSHV复制所必需的，对于逃避病毒关闭和MSC中PDGFRA驱动的发病机理所必需的。 这一发现的重要性是，通过调节氧气传感机械（O2SM） 病毒可以进入翻译起始可塑性（TRIP），定义为KSHV的能力替代 蛋白质合成，使用启动复合物eIF4E带有由pi3k-akt-调节的帽结合 MTORC1-HIF1A轴（EIF4E1盖结合）或由HIF2A调节的EIF4EH（EIF4E2盖结合）。我们 假设这赋予了KSHV的几种自适应优势：AIM 1） 病毒以最大化与多种组织相对应的不同氧气中的复制 病理生理状况，它可能使病毒绕过应激和先天免疫相关激酶 （PERK和PKR）靶向EIF2A抑制2）可以通过病毒癌基因（例如VGPCR和/或）使用。 其宿主细胞信号传导介质（例如PDGFRA）用于增殖以及直接和旁分泌的诱导 肿瘤发生目标3）可以使转化的宿主细胞在AIDS-K的背景下具有塑性和自适应 靶向PDGFRA的疗法，例如伊马替尼，已知针对PDGFRA-AKT-MTOR-E1-HIF1A 路径。