Targeting brain tumor initiating cell-specific super-enhancer associated genes to treat glioblastoma

项目总结 虽然癌症传统上被视为一种完全基于基因异常的疾病过程， 越来越多的证据表明，表观遗传改变在疾病的发生和发展中起作用。 许多类型的癌症。一个新出现的癌症表观遗传驱动因素是超级增强子，它被定义为 基因组接近的典型增强子簇。超级增强剂的重要性得到了它们的支持 通过调节谱系特异的基因表达来确定细胞状态和身份的作用， 疾病相关基因变异的丰富。从癌细胞中鉴定出的超级增强剂识别肿瘤- 多种癌症类型中的相关基因，包括多发性脑瘤。由于密切的联系 在超级增强子结构和生物功能之间，疾病特异性超级增强子的改变可能 揭示疾病发病的分子机制。 胶质母细胞瘤是最常见和最具侵袭性的原发脑瘤，对ALL的反应很差。 尽管进行了密集的研究，但仍有多种治疗方式。胶质母细胞瘤预后不良的主要原因之一 是干细胞样癌细胞的存在，通常被称为癌症干细胞。癌症干细胞在功能上 通过移植后自我更新、分化和形成肿瘤的能力来定义的。肿瘤干细胞 有助于抵抗放射和化疗，以及维持肿瘤的异质性和 血管生成。因此，肿瘤干细胞已成为设计新型治疗方法的重要靶点 战略。为了更好地了解胶质瘤干细胞特性的关键调控因素，一种原创的超级增强子筛查 已鉴定的在胶质瘤干细胞中表遗传上调且其表达上调的基因 与患者预后不良有关。 利用患者来源的胶质母细胞瘤干细胞的染色质景观分析，我确定了假定的 与患者预后不良相关的超增强剂。靶向与基因相关的基因 超级增强剂显示了生存能力的丧失，这表明了这一发现努力的潜在价值。这种方法 揭示了一组潜在的超级增强子相关基因，我建议进行进一步的研究。我会调查的 调控这些基因表达的转录因子网络，包括增强子元件， 转录因子占位，以及超级增强子结构。第二个目标将定义 超增强子相关基因在胶质瘤细胞存活、自我更新能力和肿瘤形成中的作用 体外和活体环境。第三个目标将阐明这些基因促进的分子机制。 肿瘤发生学。这些方法将使我们更好地理解定义 胶质瘤干细胞状态和新治疗方法的发展

PROJECT SUMMARY While cancer has traditionally been viewed as a disease process based exclusively on genetic aberrations, increasing evidence has demonstrated that epigenetic alterations contribute to the pathogenesis and progression of many types of cancer. One emerging epigenetic driver of cancer is the superenhancer, which is defined as a cluster of typical enhancers in close genomic proximity. The significance of superenhancers is supported by their roles in determining cell state and identity through regulation of lineage-specific gene expression, with enrichment in disease-associated genetic variation. Superenhancers identified from cancer cells identify tumor- associated genes in a number of cancer types, including multiple brain tumors. Due to the close association between superenhancer structure and biological function, alterations in disease-specific superenhancers may reveal insights into the molecular mechanisms of disease pathogenesis. Glioblastoma is the most common and most aggressive primary brain tumor, with poor responses to all therapeutic modalities despite intensive research. One major contributor to the poor prognosis of glioblastoma is the presence of stem-like cancer cells, often called cancer stem cells. Cancer stem cells are functionally defined by their abilities to self-renew, differentiate, and form tumors upon transplantation. Cancer stem cells contribute to resistance to radiation and chemotherapy, as well as maintenance of tumor heterogeneity and angiogenesis. Thus, cancer stem cells have become an important target for the design of novel therapeutic strategies. To better understand key regulators of glioma stem cell identity, an original super-enhancer screen identified genes that are epigenetically upregulated in glioma stem cells and for which elevated expression is associated with poor patient prognosis. Leveraging chromatin landscape analysis of patient-derived glioblastoma stem cells, I identified putative superenhancers that are associated with poor patient prognosis. Targeting the genes associated with the superenhancers revealed a loss of viability, suggesting potential value in this discovery effort. This approach revealed a cohort of potential super-enhancer associated genes that I propose for further study. I will investigate the transcription factor network that regulates the expression of these genes including enhancer elements, transcription factor occupancy, and super-enhancer structure. The second aim will define the role of the superenhancer-associated genes in glioma cell survival, self-renewal capacity, and tumor formation in both in vitro and in vivo settings. The third aim will elucidate the molecular mechanism by which these genes promote tumorigenesis. These approaches will lead to a greater understanding of the epigenetic features that define the glioma stem cell state and inform the development of novel therapeutics