Collaborative Activities of the Key Transcription Factors in Glioblastoma Stem-like Cancer Cells

摘要 多形性胶质母细胞瘤(GBM)患者的中位生存期距离最初只有15个月 诊断，使其成为成人脑肿瘤中最具侵袭性和致命性的形式。《世界卫生》 世界卫生组织(WHO)将GBM归类为IV级肿瘤(最高级别)，只有5%的 GBM患者在确诊后存活5年或更长时间。预后差，死亡率高 基底膜的发生率部分归因于基底膜中存在的干细胞样的肿瘤增殖细胞。 尽管这些GBM干细胞样癌群体被认为有助于治疗 耐药与肿瘤复发，干细胞诱导和肿瘤复发的潜在机制 维护，还没有完全了解。这项提案的最终目标是确定茎- 由两个关键转录因子控制的特定基因和开发新的DNA甲基化 消除GBM干细胞种群的技术。转录因子SALL2、SOX2、OLIG2 和POU3F2是将分化的GBM细胞重新编程为干细胞样瘤所必需的 正在繁殖的细胞。在这些蛋白质中，似乎只有SALL2与SOX2有物理上的相互作用。这 将是第一个评估相互作用的病理后果的调查 SALL2和SOX2，鉴定其靶基因并确定其在驱动GBM茎中的作用 人口(具体目标一)。此外，这将是第一个实验方法，准确地 靶向SALL2启动子的甲基化，阻断其表达，从而消除GBM 干细胞样癌细胞(特异性靶标II)。完成这些目标将大大增加我们的 了解GBM类干细胞是如何被诱导和维持的。我们的创新 方法将促进新的甲基化介导的治疗药物的开发 特异性抑制GBM类干细胞耐药和抑制肿瘤复发 人口。

ABSTRACT The median survival time of glioblastoma multiform (GBM) patients is only 15 months from initial diagnosis, making it the most aggressive and lethal form of adult brain tumor. The World Health Organization (WHO) classifies GBM as a grade IV tumor (the highest grade), and only 5% of the GBM patients survive 5 years or longer after diagnosis. The poor prognosis and high mortality rates of GBM are due, in part, to the stem-like tumor-propagating cells present in the GBM. Although these GBM stem-like cancer populations are believed to contribute to therapeutic resistance and cancer recurrence, the underlying mechanism of stem cell induction and maintenance, is not fully understood. The ultimate goals of this proposal are to identify stem- specific genes controlled by two key transcription factors and develop novel DNA methylation technologies to eliminate GBM stem populations. The transcription factors SALL2, SOX2, OLIG2 and POU3F2 are required for reprogramming differentiated GBM cells into stem-like tumor propagating cells. Of these proteins, only SALL2 appears to physically interact with SOX2. This will be the first investigation to evaluate the pathological consequences of the interaction between SALL2 and SOX2, identifying its target genes and determining their roles in driving GBM stem populations (Specific Aim I). In addition, this will be the first experimental approach to precisely target the SALL2 promoter for methylation, blocking its expression and thus eliminating GBM stem-like cancer cells (Specific Aim II). Completion of these aims will substantially increase our understanding of how GBM stem-like cells are induced and maintained. Our innovative approaches will facilitate the development of novel methylation-mediated therapeutics to block therapeutic resistance and inhibit tumor recurrence by specifically suppressing GBM stem-like populations.