Mechanisms of SOX2 Regulation in Glioblastoma

摘要 胶质母细胞瘤(Gb)是成人最常见的恶性原发脑肿瘤，其致命性很强。因此，有 迫切需要为这一致命疾病找到新的、有意义的治疗策略。一个主要原因是 我们目前缺乏有效的治疗方法是GB肿瘤广泛的遗传和表观遗传异质性。在 GB细胞的表观遗传多样性，积累的证据现在已经坚定地证实了临床上存在一种 GB癌细胞的重要亚群，称为GB干细胞(GSCs)，它代表一个关键细胞 用于治疗抵抗和疾病复发的底物。因此，针对肿瘤中的GSC池是一种 重要的概念战略，有可能产生新的、持久的治疗方法。我们和其他人 已经证明，与多能性相关的转录因子SOX2在 恶性GSC表型的表达，包括自我更新能力、侵袭性和体内肿瘤 成长。值得注意的是，尽管肿瘤之间存在显著的遗传异质性，SOX2在几乎 所有的GB肿瘤细胞，包括GSCs，都暗示该转录因子是GB常见的表观遗传驱动因素。 因此，识别调节GSCs中SOX2功能的机制不仅将促进我们的 在临床相关的GSC亚群中了解SOX2的基本生物学知识也导致 发现SOX2依赖的治疗靶点可能对不同GB肿瘤和细胞有效 类型。在已发表的工作和初步数据的基础上，我们将研究控制SOX2的两个关键机制 GSCs中的程序：SOX2稳定性的翻译后控制(目标1)和SOX2靶基因的规范 通过局部和远程染色质相互作用表达(目标2)。为了研究这些机制，我们将 利用两个互补的人体模型系统：一个具有良好特征的肿瘤患者库- 衍生的GSC和一种新的、同基因的、基于人类神经干细胞的GSC模型，具有明确的基因突变。 该项目的长期目标是开发新的SOX2导向的治疗策略来破坏恶性肿瘤 肿瘤生长并放大目前治疗方法的疗效。

ABSTRACT Glioblastoma (GB), the most common malignant primary brain tumor in adults, is invariably fatal. Thus, there is an urgent need to discover new and meaningful therapeutic strategies for this lethal disease. A major reason for our current lack of effective therapies is the extensive genetic and epigenetic heterogeneity of GB tumors. Within the epigenetic diversity of GB cells, accumulating evidence has now firmly established the existence of a clinically important subpopulation of GB cancer cells, called GB stem cells (GSCs), which represents a key cellular substrate for treatment resistance and disease recurrence. Thus, targeting the GSC pool in tumors is an important conceptual strategy, which has the potential to generate novel, durable treatments. We and others have previously shown that the pluripotency-related transcription factor SOX2 plays a critical role in the expression of malignant GSC phenotypes, including self-renewal capacity, invasiveness, and in vivo tumor growth. Remarkably, despite the significant genetic heterogeneity between tumors, SOX2 is expressed in almost all GB tumor cells, including GSCs, implicating this transcription factor as a common epigenetic driver in GB. Thus, the identification of the mechanisms that regulate SOX2 function in GSCs will not only advance our knowledge about the fundamental biology of SOX2 in the clinically relevant GSC subpopulation but also lead to the discovery of SOX2-dependent therapeutic targets that may be effective across different GB tumors and cell types. Based on published work and preliminary data, we will examine two key mechanisms controlling the SOX2 program in GSCs: post-translational control of SOX2 stability (Aim 1) and specification of SOX2 target gene expression through local and long-range chromatin interactions (Aim 2). To study these mechanisms, we will take advantage of two complementary human model systems: a well-characterized library of patient tumor- derived GSCs and a novel, isogenic, human neural stem cell-based GSC model with defined genetic mutations. The long-term goal of this project is to develop novel SOX2-directed therapeutic strategies to disrupt malignant tumor growth and amplify the efficacy of current treatments.