Paracrine Angiotensin II Signaling Promotes Medulloblastoma through MYC Activation

摘要 髓母细胞瘤(MB)是儿童最常见的恶性脑肿瘤，预后显著。 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 常与MYC基因扩增和/或蛋白过度表达相关，在此称为MYC- 驱动的MB。驱动MB中MYC过度激活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，很大程度上还不清楚基质是如何- 衍生信号促进MYC表达和MB生长。这代表着巨大的知识差距， 阻碍了有效的甲基溴疗法的发展。这个项目的重点是多肽激素血管紧张素II。 (AngII)，MB细胞和内皮细胞(ECs)之间致癌相互作用的介体。我们的预赛 研究发现在MB中存在一种新的旁分泌信号机制，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，Angii的促MB作用 通过沉默血管紧张素Ⅱ受体AT1R和FDA批准的AT1R阻滞剂(ARB)替米沙坦来抑制， 支持ARBS用于MB血管紧张素Ⅱ信号转导的临床靶向的可行性。要了解 分子机制，我们在MB细胞中发现了一个新的AT1R-MYC正反馈环，由此Angii MYC通过AT1R诱导MYC表达，MYC诱导AT1R表达形成正反馈环。 总体而言，这些初步数据支持我们的中心假设，即血管紧张素转换酶介导致癌肿瘤- 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 循环播放。本项目将更全面地研究这一新的功能和分子机制 MB中的AngiI-AT1R-MYC信号通路。我们还将研究系统地治疗跨境ARB 临床前MB模型中的血脑屏障。我们将重点关注两个具体目标。目标1是确定Angii是否 通过AT1R-MYC正反馈环促进MB细胞的致瘤性。目标2是改变AT1R的用途 抑制MB生长和抑制肿瘤中MYC表达的阻滞剂。如果成功，我们将发现一部小说 旁分泌信号机制，导致MYC过度激活并促进MB细胞的致瘤性。我们 将在MB模型中进行两种ARB的第一次药效研究。更重要的是，我们将定义ARB- 诱导MB异种移植瘤和基质细胞的转录组改变。这些结果将证明 促进使用ARB和可能针对Angii信号通路的其他药物的MB临床试验。

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.