Evaluating ADGRB3 as a tumor suppressor epigenetically silenced in WNT medulloblastoma

评估 ADGRB3 作为 WNT 髓母细胞瘤中表观遗传沉默的肿瘤抑制因子

• 批准号: 10057681
• 负责人: ERWIN G VAN MEIR
• 金额: $ 42.51万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10057681
• 关键词: Evaluating; ADGRB3; tumor; suppressor; epigenetically

PROJECT SUMMARY: No changes from initial submission There is an urgent need to develop novel therapies for patients with medulloblastoma (MB), the most common malignant central nervous system (CNS) tumor in children. Current treatments include surgery, radiotherapy, and chemotherapy and result in 5-year survival rates of 40-90% depending on subtype. However, children suffer important morbidity secondary to treatment, including neurological, intellectual and physical disabilities. The overall purpose of the present project is to investigate the role of the ADGRB3 receptor in susceptibility of cerebellar transformation, and explore new therapies for MB based on the related mechanisms. ADGRB3 is an orphan seven transmembrane G protein-coupled receptor (GPCR) specifically expressed in the brain, and belonging to the adhesion-type sub-family. Our new preliminary data show that ADGRB3 expression is significantly reduced in patients with MBs of the WNT group, and the promoter is epigenetically silenced, suggesting that ADGRB3 loss may facilitate WNT-MB formation. We present evidence for the involvement of methylated CpG binding protein MBD2 and histone methyltransferase EZH2 in switch to a silent chromatin. Moreover, we show that reactivation of ADGRB3 can reduce cell proliferation and tumor growth, supporting a tumor suppressive role. To test this in the physiological setting, we generated ADGRB3 knockout (KO) mice, which we plan to cross with mice expressing mutant b-catenin in neural progenitors of the rhombic lip and dorsal brainstem, which are the cells of origin of WNT-MB. Based on these results, we hypothesize that ADGRB3 is a tumor suppressor in the cerebellum and that restoration of its expression with epigenetic therapy may represent a novel therapeutic intervention for children with WNT-MB. To test our hypothesis, we propose the following aims: (i) identify and target the epigenetic mechanism(s) underlying ADGRB3 gene silencing in WNT-MB, (ii) determine whether and how restoration of ADGRB3 expression can inhibit MB cell growth, oncogenic signaling and tumorigenic properties, and (iii) determine whether loss of ADGRB3 gene expression in the background of oncogenic Ctnnb1 activation predisposes mice to cerebellar transformation and MB tumor development. These studies are important as they increase our knowledge about developmental neurobiology in the CNS, and may lead to the development of novel therapeutic approaches for patients with medulloblastoma.

项目摘要：与初次提交相比没有变化 迫切需要为髓母细胞瘤（MB）患者开发新疗法，髓母细胞瘤是最常见的肿瘤 儿童恶性中枢神经系统（CNS）肿瘤。目前的治疗方法包括手术、放射治疗、 和化疗，根据亚型的不同，5 年生存率为 40-90%。然而，儿童 遭受治疗后继发的严重并发症，包括神经、智力和身体残疾。 本项目的总体目的是研究 ADGRB3 受体在易感性中的作用 探讨小脑转化的机制，并根据相关机制探索MB的新疗法。 ADGRB3 是一种孤儿七跨膜 G 蛋白偶联受体 (GPCR)，在大脑中特异性表达， 属于粘附型亚科。我们新的初步数据表明 ADGRB3 表达是 WNT组MBs患者明显减少，启动子表观遗传沉默， 表明 ADGRB3 丢失可能促进 WNT-MB 的形成。我们提供参与的证据 甲基化 CpG 结合蛋白 MBD2 和组蛋白甲基转移酶 EZH2 转为沉默 染色质。此外，我们表明 ADGRB3 的重新激活可以减少细胞增殖和肿瘤生长， 支持肿瘤抑制作用。为了在生理环境中测试这一点，我们生成了 ADGRB3 敲除 （KO）小鼠，我们计划将其与在神经祖细胞中表达突变b-连环蛋白的小鼠杂交 菱形唇和背侧脑干，它们是WNT-MB的起源细胞。根据这些结果，我们 假设 ADGRB3 是小脑中的肿瘤抑制因子，并且通过恢复其表达 表观遗传疗法可能代表了 WNT-MB 儿童的一种新型治疗干预措施。来测试我们的 假设，我们提出以下目标：（i）识别并针对潜在的表观遗传机制 WNT-MB 中 ADGRB3 基因沉默，(ii) 确定 ADGRB3 表达是否以及如何恢复 可以抑制 MB 细胞生长、致癌信号传导和致瘤特性，以及 (iii) 确定是否丢失 ADGRB3基因表达在致癌Ctnnb1激活背景下使小鼠易患小脑 转化和MB肿瘤的发展。这些研究很重要，因为它们增加了我们的知识 关于中枢神经系统发育神经生物学，并可能导致新治疗方法的开发 髓母细胞瘤患者的治疗方法。