Oncogenic mechanisms underlying GLI2-amplified medulloblastoma

项目摘要 髓母细胞瘤是儿童最常见的恶性脑肿瘤。MB有几个子类型， 其中，GLI2扩增的SHH-MB亚型预后最差，存活率最低； 一年存活率为30%。此外，GLI2扩增的MBS对唯一的靶向治疗没有反应 可供SMO抑制剂SHH-MB选择。这留下了一个尚未填补的危重治疗缺口，而且存在 迫切需要确定新的靶点来开发有效的治疗方法。然而，更深入地了解 GLI2扩增的MB肿瘤发生的细胞和分子机制目前尚不清楚。以一种专注的 目的为了解决这种特殊类型的MB肿瘤的发生，我们最近建立了一种转基因小鼠模型 GLI2驱动的MB。利用这个模型，我们证明了GLI2是肿瘤发生的关键驱动因素，并发现 颗粒细胞祖细胞(GCPs)为起源细胞。有趣的是，我们还发现GLI2只驱动 Math1+胚胎GCPs而不是新生儿GCPs形成SHH-MB。相应地，我们的scRNA-seq分析 研究发现，MAPK通路在胚胎细胞中特异富含，而在新生儿Math1+GCPs中不表达。此外， MAPK通路在小鼠和人GLI2驱动的MB肿瘤中被激活，并被MEK/ERK抑制剂激活 显著延缓GLI2驱动的MB在体内的生长。基于这些令人兴奋的初步数据，我们把 提出了一种新的假设，即GLI2驱动的MB起源于Math1+的特定细胞群体 GCP和在小脑发育过程中的特定时空窗口。因此，目标是 胚胎GCPs中MAPK/MEK/ERK通路在特定时间段可有效阻止GLI2- 驱动甲基溴的启动和进展。在这项提案中，我们计划使用我们新的GLI2驱动的MB转基因 小鼠模型更准确地定义GLI2驱动MB的肿瘤发生的时空窗口 确定GLI2驱动的MB的启动和发育是否需要MAPK/MEK/ERK信号。 此外，我们将使用GLI2扩增的MB患者来源的异种移植(PDX)模型来评估 MEK/ERK抑制剂在阻止肿瘤进展和研究治疗机制中的作用 抵抗。我们将追求设计新疗法和取得更好治疗效果的终极目标。 通过靶向MAPK/MEK/ERK通路和寻找更多的联合治疗机会 抗击肿瘤复发。由于GLI2的异常表达在许多其他类型的肿瘤中也存在，我们的 研究还将为所有由GLI2驱动的恶性肿瘤开创先例。

Project Summary Medulloblastoma (MB) is the most common malignant brain tumor in children. There are several subtypes of MB, and among them, the GLI2-amplified SHH-MB subtype has the worst prognosis and a poor survival rate; the 5- year survival rate is <30%. Moreover, the GLI2-amplified MBs are non-responsive to the only targeted treatment option available for SHH-MB, the SMO inhibitors. This leaves an unmet critical treatment gap, and there is an urgent need to identify novel targets to develop effective therapeutics. However, a deeper understanding of the cellular and molecular mechanisms driving GLI2-amplified MB tumorigenesis is currently lacking. With a focused goal to resolve this particular type of MB tumorigenesis, we recently generated an engineered mouse model of GLI2-driven MB. Using this model, we demonstrated that GLI2 is the critical driver of tumorigenesis and identified granule cell progenitors (GCPs) as the cells of origin. Interestingly, we have also found that GLI2 drives only Math1+ embryonic GCPs but not neonatal GCPs to form SHH-MB. Correspondingly, our scRNA-seq analysis revealed that the MAPK pathway is specifically enriched in embryonic but not neonatal Math1+ GCPs. Moreover, the MAPK pathway is activated in mouse and human GLI2-driven MB tumors, and a MEK/ERK inhibitor significantly delayed the growth of GLI2-driven MB in vivo. Based on these exciting preliminary data, we put forward a novel hypothesis that GLI2-driven MB originates from a specific cell population of Math1+ GCPs and in a particular spatiotemporal window during cerebellar development. Therefore, targeting MAPK/MEK/ERK pathway in the embryonic GCPs in a specific timeframe can effectively prevent GLI2- driven MB initiation and progression. In this proposal, we plan to use our new GLI2-driven MB transgenic mouse model to define the spatiotemporal window of tumorigenesis of GLI2-driven MB more precisely and establish whether MAPK/MEK/ERK signaling is required for GLI2-driven MB initiation and development. Furthermore, we will use GLI2-amplified MB patient-derived xenograft (PDX) models to evaluate the efficacy of MEK/ERK inhibitors in preventing tumor progression and examine the mechanisms underlying therapeutic resistance. We will pursue our ultimate goal to design novel therapeutics and achieve better treatment outcomes by targeting MAPK/MEK/ERK pathway and via identifying additional combinational therapeutic opportunities to fight against tumor relapse. Since aberrant expression of GLI2 occurs in a number of other tumor types, our studies will also set a precedent for all GLI2-driven malignancies.