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: 10400674
• 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/10400674
• 关键词: Adult; Automobile Driving; Binding; Biological Assay; Brain Neoplasms; Breast Carcinoma; CRISPR/Cas technology; Candidate Disease Gene; Cell Line; Cells; Chimeric Proteins; 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; Recurrence; Reporting; Repression; Role; Serum; Technology; Testing; Therapeutic; Time; Western Blotting; World Health Organization; base; 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 胶质母细胞瘤多形（GBM）患者的中位生存时间从初始开始仅15个月 诊断，使其成为成人脑肿瘤的最具侵略性和致命形式。世界健康 组织（WHO）将GBM归类为IV级肿瘤（最高级），只有5％ GBM患者诊断后5年或更长时间存活。预后不良和高死亡率 GBM的速率部分归因于GBM中存在的茎样肿瘤细胞。 尽管这些类似GBM的癌症种群被认为有助于治疗 抗性和癌症复发，干细胞诱导的潜在机制和 维护，尚未完全理解。该提案的最终目标是确定词干 由两个关键转录因子控制并发展出新型DNA甲基化的特定基因 消除GBM STEM种群的技术。转录因子sall2，sox2，olig2 将分化的GBM细胞重编程为茎样肿瘤所必需的POU3F2 传播细胞。在这些蛋白质中，只有SALL2似乎与SOX2物理相互作用。这 将是评估相互作用的病理后果的首次研究 sall2和sox2，识别其靶基因并确定其在驱动GBM茎中的作用 种群（特定目的I）。此外，这将是第一种精确的实验方法 靶向SALL2启动子进行甲基化，阻断其表达，从而消除GBM 茎状癌细胞（特定的目标II）。这些目标的完成将大大增加我们的 了解如何诱导和维持GBM干细胞。我们的创新性 方法将有助于开发新型甲基化介导的治疗剂以阻止 治疗性抗性和通过特异性抑制GBM茎样抑制肿瘤复发 人群。