Isolation, characterization and translational development of glioma stem cells

神经胶质瘤干细胞的分离、表征和转化发育

• 批准号: 10337037
• 负责人: Luis Fernando Parada
• 金额: $ 105.6万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337037
• 关键词: Adult; Astrocytes; Biological; Cells; Chemicals; Data; Dependence; Development; Developmental Biology; Disease; Embryo; Event; Fibroblasts; Gene Expression Profile; Genes; Genetically Engineered Mouse; Genotype; Glioblastoma; Glioma; Growth; Human; Lead; Malignant Neoplasms; Modeling; Molecular; Mus; Mutate; Mutation; NF1 gene; Neonatal; Neurosciences; Oncogenes; PTEN gene; Pathway interactions; Pattern; Phenotype; Population; Public Health; Research; Solid Neoplasm; Stratification; Suppressor Mutations; TP53 gene; Toxic effect; Tumor Suppressor Proteins; Tumor-Derived; cancer cell; cancer stem cell; driver mutation; improved; in vivo; insight; mouse model; nanomolar; neoplastic cell; novel; novel strategies; patient derived xenograft model; programs; small molecule; stem; stem cells; therapeutic development; therapy development; tool; tumor; tumorigenic

Project Summary/Abstract Solid tumors arise as the consequence of accumulation of oncogene and/or tumor suppressor mutations. How these mutations arise and accumulate in one cell over a lifetime remains a mystery. It is likely that an improved understanding of the early events that form a pre-tumorigenic cell could have implications for analysis of mature tumor cells and insights into improved therapy development. We have developed fully penetrant genetically engineered mouse models of glioblastoma multiforme (GBM) by mutation of three tumor suppressors commonly found mutated in human GBM (P53, PTEN, & NF1). Using our combined background in developmental biology and neuroscience, we have traced the origin of these tumors to the adult stem/progenitor cell population. We have developed tools to uncover functional GBM subtypes that are predicated on the tumor cell of origin rather than on specific driver mutations (Alcantara, Cancer Cell, 2015). These studies will be extended to identify cell of origin and relationship to genotype and phenotype. Moreover, using gene expression signatures from the novel mouse GBM subtypes, we have identified human GBM counterpart signatures that suggest similar biological origins and a novel strategy for human GBM molecular stratification. Our data provide evidence for additional human GBM subtypes that may also relate to novel cells of origin. The mouse models demonstrate an endogenous GBM tumor cell hierarchy placing a cancer stem cell at the apex. Our ongoing studies suggest that each of the new stratified GBM subtypes are governed by a cancer stem cell pattern of growth. We will expand and confirm these observations. Using a phenotypic high throughput small chemical compound screen we have identified small molecules that have nanomolar toxicity on primary low passage GBM derived cells but not on primary normally dividing cells such as mouse embryo fibroblasts or neonatal astrocytes. In addition, lead compounds including a benzimidazolium compound and its derivatives demonstrate toxicity on primary human GBM derived tumor spheres. These compounds hold promise for in vivo studies and identifying novel key GBM dependency pathways for therapeutic development. We are developing a comprehensive GBM patient derived xenograft program that will be employed to further validate our mouse model finding and to identify, isolate and neutralize human GBM cancer stem cells.

项目摘要/摘要 实体瘤是由于癌基因和/或肿瘤抑制突变的积累而产生的。 这些突变是如何在一生中在一个细胞中积聚的，仍然是一个谜。很可能 对形成染色体前细胞形成早期事件的早期事件的理解可能对 分析成熟的肿瘤细胞和对改善治疗发展的见解。我们已经完全发展 胶质母细胞瘤多形（GBM）的渗透性基因工程小鼠模型通过三个突变 通常发现在人GBM中突变的肿瘤抑制剂（p53，PTEN和NF1）。使用我们的组合 发育生物学和神经科学的背景，我们将这些肿瘤的起源追溯到 成人茎/祖细胞群。我们开发了工具来发现功能性的GBM亚型 基于原始肿瘤细胞而不是特定的驱动突变（Alcantara，Cancer Cell，2015）。 这些研究将扩展以鉴定来源细胞以及与基因型和表型的关系。 此外，使用新型小鼠GBM亚型的基因表达特征，我们已经确定了 人类GBM对应着签名，暗示了类似的生物学起源和人类的新型策略 GBM分子分层。我们的数据提供了其他人类GBM亚型的证据 与新颖的原点细胞有关。小鼠模型显示了内源性GBM肿瘤细胞层次结构 将癌症干细胞放在顶点。我们正在进行的研究表明，每个新的分层GBM 亚型受生长的癌症干细胞模式控制。我们将扩展并确认这些 观察。使用表型高吞吐量小化学化合物屏幕，我们已经确定了小的 在原代低通道GBM衍生细胞上具有纳摩尔毒性的分子，而不是原发性的 通常将细胞（例如小鼠胚胎成纤维细胞或新生儿星形胶质细胞）进行。另外，铅 包括苯咪唑化合物及其衍生物在内的化合物表现出对主要的毒性 人类GBM衍生的肿瘤球。这些化合物对体内研究并识别新颖的化合物有望 关键的GBM治疗发展依赖途径。我们正在开发全面的GBM 患者衍生的异种移植计划将用于进一步验证我们的鼠标模型查找和 识别，分离和中和人类GBM癌症干细胞。