Paracrine Angiotensin II Signaling Promotes Medulloblastoma through MYC Activation

旁分泌血管紧张素 II 信号通过 MYC 激活促进髓母细胞瘤

• 批准号: 9751414
• 负责人: Mingyao Ying
• 金额: $ 20.22万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751414
• 关键词: Angiotensin II; Angiotensin II Receptor; Angiotensin II Signaling Pathway; Blood - brain barrier anatomy; Cell Communication; Cell Proliferation; Cells; Cessation of life; Childhood Malignant Brain Tumor; Clinical; Clinical Trials; Data; Development; Drug Targeting; Endothelial Cells; Exposure to; FDA approved; Feedback; Foundations; Gene Expression; Genetic Transcription; Genomics; Goals; Growth; Human; Inflammation; Inflammatory; Intellectual functioning disability; Knowledge; Losartan; MYC Gene Amplification; MYC gene; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Mutation; Neurologic; Oncogenic; Paracrine Communication; Pathway interactions; Peptidyl-Dipeptidase A; Pharmaceutical Preparations; Physically Handicapped; Protein Overexpression; Renin; Role; SHH gene; Signal Pathway; Signal Transduction; Solid; Stromal Cells; Testing; Therapeutic; Tumor Angiogenesis; Tumorigenicity; Xenograft procedure; base; brain cell; c-myc Genes; cell growth; clinically translatable; drug efficacy; efficacy study; genetic signature; hypertension treatment; induced pluripotent stem cell; insight; medulloblastoma; medulloblastoma cell line; migration; neoplastic cell; new therapeutic target; non-genetic; novel; paracrine; peptide hormone; pre-clinical; success; telmisartan; transcriptome; tumor

Summary Medulloblastoma (MB) is the most common malignant pediatric brain tumor, and results in significant neurological, intellectual and physical disability or death. Group 3 MB, the most aggressive subtype, is frequently associated with MYC gene amplification and/or protein overexpression, hereby referred to as MYC- driven MB. The molecular mechanisms that drive MYC hyper-activation in MB remain incompletely understood. MB cells in actual tumors interact extensively with stromal cells. However, it is largely unknown how stroma- derived signals promote MYC expression and MB growth. This represents a substantial knowledge gap and hinders the development of effective MB therapies. This project focuses on the peptide hormone Angiotensin II (AngII), a mediator of the oncogenic interactions between MB cells and endothelial cells (ECs). Our preliminary studies identified a novel paracrine signaling mechanism in MB, where EC-released AngII induces MYC expression in MB cells and promotes MB cell growth. We further found that the MB-promoting effects of AngII are inhibited by silencing the AngII receptor AT1R and the FDA-approved AT1R blocker (ARB) Telmisartan, supporting the feasibility to use ARBs for clinical targeting of the AngII signaling in MB. To understand the molecular mechanisms, we identified a novel AT1R-MYC positive feedback loop in MB cells whereby AngII induces MYC expression through AT1R, and MYC induces AT1R expression to form a positive feedback loop. Overall, these preliminary data support our central hypothesis that AngII mediates oncogenic tumor- endothelial-cell interactions that promote MB cell tumorigenicity by activating a AT1R-MYC positive feedback loop. This project will more comprehensively study the functions and molecular mechanisms of this novel AngII-AT1R-MYC signaling pathway in MB. We will also study the systemic treatment of ARBs that cross the blood-brain barrier in pre-clinical MB models. We will focus on two specific aims. Aim 1 is to determine if AngII promotes MB cell tumorigenicity through a AT1R-MYC positive feedback loop. Aim 2 is to repurpose AT1R blockers to inhibit MB growth and suppress MYC expression in tumors. If successful, we will uncover a novel paracrine signaling mechanism that causes MYC hyper-activation and promotes MB cell tumorigenicity. We will perform the first drug efficacy study of two ARBs in MB models. More significantly, we will define ARB- induced transcriptome changes in tumor and stromal cells in MB xenografts. These results will justify and facilitate MB clinical trials using ARBs and likely other drugs targeting the AngII signaling pathway.

总结 髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤， 神经、智力和身体残疾或死亡。第3组MB是最具攻击性的亚型， 通常与MYC基因扩增和/或蛋白质过表达相关，在此称为MYC- 驱动MB驱动MB中MYC超活化的分子机制仍不完全清楚。 实际肿瘤中的MB细胞与基质细胞广泛相互作用。然而，很大程度上不知道基质是如何- 衍生的信号促进MYC表达和MB生长。这是一个巨大的知识差距， 阻碍了有效MB疗法的发展。该项目的重点是肽激素血管紧张素II 血管生成素II（AngII）是MB细胞和内皮细胞（EC）之间致癌相互作用的介质。我们的初步 研究确定了MB中一种新的旁分泌信号机制，其中EC释放的AngII诱导MYC 在MB细胞中表达并促进MB细胞生长。我们进一步发现，血管紧张素II促进心肌细胞增殖的作用， 通过沉默AngII受体AT1R和FDA批准的AT1R阻断剂（ARB）替米沙坦来抑制， 支持将ARB用于MB中AngII信号传导的临床靶向的可行性。了解 分子机制，我们在MB细胞中鉴定了一种新的AT1R-MYC正反馈环， 通过AT1R诱导MYC表达，MYC诱导AT1R表达形成正反馈环。 总的来说，这些初步数据支持我们的中心假设，即AngII介导致癌肿瘤- 通过激活AT1R-MYC正反馈促进MB细胞致瘤性的内皮-细胞相互作用 循环.本项目将更全面地研究这一新颖的功能和分子机制 MB中的AngII-AT1R-MYC信号通路。我们还将研究跨性别的ARB的系统治疗。 临床前MB模型中的血脑屏障。我们将着重于两个具体目标。目的1是确定AngII是否 通过AT1R-MYC正反馈环促进MB细胞致瘤性。目标2：重新利用AT1R 阻断剂以抑制MB生长并抑制肿瘤中MYC表达。如果成功了，我们将发现一部 这是导致MYC过度活化并促进MB细胞致瘤性的旁分泌信号传导机制。我们 将在MB模型中进行两种ARB的首次药物疗效研究。更重要的是，我们将定义ARB- 诱导MB异种移植物中肿瘤和基质细胞的转录组变化。这些结果将证明， 促进使用ARB和其他可能靶向AngII信号通路的药物的MB临床试验。