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.

摘要 多形性胶质母细胞瘤（GBM）患者的中位生存时间仅为15个月， 诊断，使其成为最具侵略性和致命形式的成人脑肿瘤。世界卫生 世界卫生组织（WHO）将GBM分类为IV级肿瘤（最高级别），并且只有5%的GBM患者是IV级肿瘤。 GBM患者在诊断后存活5年或更长时间。预后差，死亡率高 GBM的发病率部分是由于GBM中存在的干细胞样肿瘤增殖细胞。 尽管这些GBM干细胞样癌症人群被认为有助于治疗性肿瘤， 耐药性和癌症复发，干细胞诱导的潜在机制， 维护，并没有完全理解。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，并开发新的DNA甲基化 技术来消除GBM干细胞群体。转录因子SALL 2、SOX 2、OLIG 2 和POU 3F 2是将分化的GBM细胞重编程为干细胞样肿瘤所必需的 繁殖细胞在这些蛋白质中，只有SALL 2似乎与SOX 2发生物理相互作用。这 这将是第一次研究，以评估病理后果的相互作用， SALL 2和SOX 2，鉴定其靶基因并确定其在驱动GBM干细胞中的作用 具体目标（一）。此外，这将是第一个实验性的方法， 靶向SALL 2启动子进行甲基化，阻断其表达，从而消除GBM 干细胞样癌细胞（特定目标II）。实现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 这些方法将有助于开发新的甲基化介导的治疗方法， 通过特异性抑制GBM干细胞样抑制肿瘤复发 人口。