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肉瘤形成的认识不断提高， 在这些进展的基础上实施合理设计的治疗，晚期AIDS-KS主要是一种 无法治愈的疾病和许多最有前途的新疗法仍然存在重大障碍， 实施问题，特别是在艺术的设置。我们的实验室作出了重大贡献， 阐明了病毒致癌机制及其引起的宿主致癌机制， 实施潜在的治疗方法。在这个R 01的最后一个周期：1）我们已经表明，KSHV 裂解基因;特别是vGPCR癌基因可以诱导PDGF介导的PDGFRA活化， PDGFRA是AIDS-KS中最显著激活的RTK，其是致癌驱动因子和治疗剂。 在伊马替尼试验中显示出临床威力的AIDS-KS靶点。2)基于PDGFRA是 KSHV招募的一个关键致癌途径，我们推断致癌KS祖细胞应该是一个 PDGFRA（+）细胞。这导致我们鉴定PDGFRA间充质干细胞为KS祖细胞， PDGFRA不仅是一种表型标志物，而且是血管生成性KS-1中KSHV肿瘤发生的促进因素。 比如环境。这一发现导致了一种新的KSHV感染-肿瘤发生系统的发展， 允许剖析血管生成微环境的影响以及病毒和宿主的贡献 3）我们发现KSHV调节肿瘤发生的能力， 氧感应机制允许病毒利用低氧调节的交替翻译起始 eIF 4 EH由HIF 2a激活，并由eIF 4 E2帽结合蛋白介导，我们发现， 对于KSHV复制，对于逃避病毒关闭和对于MSC中PDGFRA驱动的发病机制是必需的。 这一发现的重要性在于，通过其对氧传感机制（O2 SM）的调节， 翻译起始可塑性（translation initiation plasticity，TRIP）是指KSHV能够选择性地启动 使用起始复合物eIF 4 E和蛋白质合成， mTORC 1-HIF 1a轴（eIF 4 E1帽结合）或受HIF 2a调节的eIF 4 EH（eIF 4 E2帽结合）。我们 假设这赋予了KSHV几个适应性优势，我们将在以下方面进行研究：目的1）它允许 病毒在对应于各种组织的不同氧水平下最大化复制， 病理生理条件和它可能允许病毒绕过压力和先天免疫相关激酶 (PERK和PKR）靶向的eIF 2a抑制2）它可以被病毒致癌基因如vGPCR和/或 其宿主细胞信号传导介质如PDGFRA用于增殖和诱导直接和旁分泌 肿瘤发生目的3）可以使转化的宿主细胞在AIDS-KS的背景下具有可塑性和适应性 靶向PDGFRA的治疗，如伊马替尼，已知靶向PDGFRA-AKT-mTOR-E1-HIF 1a 通路