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

胶质母细胞瘤干细胞样癌细胞中关键转录因子的协同活动

• 批准号: 10595049
• 负责人: Chang Kyoo Sung
• 金额: $ 10.35万
• 依托单位: TEXAS A&M UNIVERSITY-KINGSVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595049
• 关键词: Adult; Automobile Driving; Binding; Biological Assay; Brain Neoplasms; Breast Carcinoma; CRISPR/Cas technology; Candidate Disease Gene; Cell Line; Cells; Chimeric Proteins; Classification; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Colon Carcinoma; Complex; CpG Islands; DNA Methylation; Development; Diagnosis; Disease Progression; Engineering; Flow Cytometry; Gene Expression; Generations; Genes; Genetic Transcription; Glioblastoma; Glioma; Goals; Human; Hypermethylation; Investigation; Knock-out; Maintenance; Malignant Neoplasms; Measures; Mediating; Methylation; Methyltransferase; Ovarian Carcinoma; Pancreatic carcinoma; Pathologic; Pathway interactions; Patients; Population; Prognosis; Property; Prostate carcinoma; Proteins; Recurrent Malignant Neoplasm; Recurrent tumor; Reporting; Repression; Role; Serum; Technology; Testing; Therapeutic; Time; Western Blotting; World Health Organization; cancer cell; cancer recurrence; cell motility; experimental study; glioma cell line; innovation; mortality; mutant; novel; novel strategies; novel therapeutic intervention; promoter; pyrosequencing; self-renewal; stem; stem cell biomarkers; stem cells; stem-like cell; stemness; therapy resistant; transcription factor; transcriptome sequencing; tumor; tumor initiation; vector

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.

抽象的 多形性胶质母细胞瘤 (GBM) 患者的中位生存时间从最初开始仅 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列为IV级肿瘤（最高级别），仅占5% GBM 患者在诊断后可存活 5 年或更长时间。预后差、死亡率高 GBM 的发生率部分归因于 GBM 中存在的干细胞样肿瘤增殖细胞。 尽管这些 GBM 干细胞样癌症群体被认为有助于治疗 耐药性和癌症复发、干细胞诱导的潜在机制和 维护，不完全了解。该提案的最终目标是确定干 由两个关键转录因子控制的特定基因并产生新的 DNA 甲基化 消除 GBM 干细胞群的技术。转录因子 SALL2、SOX2、OLIG2 和 POU3F2 是将分化的 GBM 细胞重编程为干细胞样肿瘤所必需的 增殖细胞。在这些蛋白质中，只有 SALL2 似乎与 SOX2 发生物理相互作用。这 将是第一个评估之间相互作用的病理后果的调查 SALL2 和 SOX2，识别其靶基因并确定它们在驱动 GBM 干细胞中的作用 人口（具体目标 I）。此外，这将是第一个精确地进行实验的方法 靶向 SALL2 启动子甲基化，阻断其表达，从而消除 GBM 干细胞样癌细胞（具体目标 II）。完成这些目标将大大提高我们的 了解 GBM 干细胞样细胞是如何诱导和维持的。我们的创新 方法将促进新型甲基化介导疗法的开发，以阻断 通过特异性抑制 GBM 干细胞样细胞来抑制治疗耐药性并抑制肿瘤复发 人口。