Identification and targeting of mechanisms specific to glioma stem cells in glioblastoma

胶质母细胞瘤中胶质瘤干细胞特异性机制的鉴定和靶向

• 批准号: 10434100
• 负责人: DANIEL J BRAT
• 金额: $ 35.57万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434100
• 关键词: Automobile Driving; BRAT gene; Behavior; Biological; Biology; Brain Neoplasms; CDK5 gene; CXCR4 gene; Cell division; Cells; Data; Daughter; Development; Drosophila genus; Dyes; Equilibrium; Gene Targeting; Genes; Genetic; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Growth; Human; Hypoxia; In Vitro; Lasers; Lead; Malignant - descriptor; Malignant Glioma; Malignant neoplasm of brain; Microscopic; Molecular; Mus; Mutate; Necrosis; Necrosis Induction; Neoplasms; Nervous system structure; Orthologous Gene; Pathway interactions; Pattern; Pharmacology; Phenotype; Primary Brain Neoplasms; Process; Prognosis; Property; Recurrence; Rose Bengal; Self-Direction; Signal Transduction; Study models; System; Techniques; Therapeutic; Thrombosis; Time; Tumor Stem Cells; Tumor Suppressor Proteins; Tumorigenicity; Up-Regulation; Work; Xenograft Model; Xenograft procedure; cranium; daughter cell; human model; in vivo; in vivo Model; inhibitor; migration; mouse model; multiphoton microscopy; neoplastic; neoplastic cell; nestin protein; neuroblast; novel; novel therapeutics; photoactivation; pluripotency; pre-clinical; programs; response; self-renewal; stem; stem cell expansion; stem cell function; stem cells; stemness; targeted treatment; therapeutic target; therapy resistant; treatment strategy; tumor growth; tumor microenvironment

Project Summary/Abstract Glioblastoma (GBM) is the most common and most malignant primary brain tumor and has a dismal prognosis. Abundant evidence now indicates that a small subset of neoplastic cells, referred to as Glioma Stem Cells (GSCs), governs biologic behavior and resistance to therapy. GSCs inhabit specific biologic niches and have properties of self-renewal, pluripotency and high tumorigenicity. They can be identified by expression of markers, such as CD133, CD15 and nestin, yet molecular mechanisms responsible for their specific stem-like behavior in glioblastomas have not been fully defined. This proposal aims to define mechanisms underlying fundamental biological properties of GSCs, including: 1) their marked accumulation following the development of necrosis and tendency to localize to the hypoxic niche; and 2) a disrupted program of asymmetric cell division that favors self-renewing division over differentiation. We have developed novel in vitro and in vivo models and analytic techniques to study the differential behavior of stem and non-stem glioma cells within the tumor micro-environment, especially as it relates to their accumulation in regions of hypoxia. These include an in vivo orthotopic xenograft model in which stem cells are interrogated for patterns and mechanisms of accumulation following the induction of necrosis using a photo-activated dye. We also dissect pathways that direct asymmetric cellular division in Drosophila nervous system provide clues to understand the stem/non-stem dynamics in malignant gliomas. We have previously demonstrated that the human ortholog of Drosophila Brat, Trim3, is a tumor suppressor that regulates glioma stem cell dynamics and promotes stemness when lost. Here we propose to investigate novel regulatory mechanisms that arise during transition to the stem cell phenotype that can be antagonized therapeutically. Regulatory networks and potential therapeutic targets are further explored in xenografts and genetically engineered mouse models that recapitulates human gliomas to show efficacy.

项目概要/摘要 胶质母细胞瘤（GBM）是最常见、恶性程度最高的原发性脑肿瘤， 预后不佳。现在大量证据表明一小部分 肿瘤细胞，称为神经胶质瘤干细胞 (GSC)，控制生物行为 和对治疗的抵抗力。 GSC 栖息于特定的生物生态位并具有以下特性： 自我更新、多能性和高致瘤性。可以通过表情来识别 标记物，例如 CD133、CD15 和巢蛋白，但负责的分子机制 由于它们在胶质母细胞瘤中的特定干细胞样行为尚未完全确定。这 该提案旨在定义基本生物学特性的机制 GSC，包括：1) 坏死后显着积累 以及定位于缺氧生态位的倾向； 2）不对称的中断程序 细胞分裂有利于自我更新分裂而不是分化。我们开发了 用于研究差异的新型体外和体内模型和分析技术 肿瘤微环境中干细胞和非干胶质瘤细胞的行为， 特别是因为它与它们在缺氧区域的积累有关。其中包括一个在 体内原位异种移植模型，其中干细胞被询问模式和 使用光激活诱导坏死后的积累机制 染料。我们还剖析了果蝇中指导不对称细胞分裂的途径 神经系统为理解恶性疾病的干/非干动力学提供了线索 神经胶质瘤。我们之前已经证明，果蝇 Brat 的人类直系同源物， Trim3 是一种肿瘤抑制因子，可调节神经胶质瘤干细胞动力学并促进 失去时的干性。在这里，我们建议研究新的监管机制 在向干细胞表型转变期间出现，可被拮抗 治疗上。监管网络和潜在的治疗靶点正在进一步 在异种移植和基因工程小鼠模型中进行了探索，概括了 人类神经胶质瘤显示疗效。

项目成果

cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas.

• DOI: 10.1007/s00401-020-02127-9
• 发表时间: 2020-03
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Brat DJ;Aldape K;Colman H;Figrarella-Branger D;Fuller GN;Giannini C;Holland EC;Jenkins RB;Kleinschmidt-DeMasters B;Komori T;Kros JM;Louis DN;McLean C;Perry A;Reifenberger G;Sarkar C;Stupp R;van den Bent MJ;von Deimling A;Weller M
• 通讯作者: Weller M