Notch signaling in brain tumors

脑肿瘤中的Notch信号传导

• 批准号: 7437255
• 负责人: Charles G Eberhart
• 金额: $ 35.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7437255
• 关键词: Apoptosis; Biology; Brain; Brain Neoplasms; Cell Line; Cell Proliferation; Cell Survival; Cells; Child; Chimera organism; Choroid Plexus Neoplasms; Development; Fetal Development; Genes; Glioma; Goals; Growth; Human; In Vitro; Ligands; Malignant neoplasm of brain; Mus; Mutation; Neoplasms; Notch Signaling Pathway; Oncogenes; Pathway interactions; Property; Protein Overexpression; Resected; Role; Signal Transduction; Squamous cell carcinoma; Stem cells; System; T-Cell Leukemia; Testing; Tumor Stem Cells; base; cancer type; insight; medulloblastoma; neoplastic cell; nerve stem cell; notch protein; novel therapeutics; precursor cell; receptor; stem; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): The goal of this proposal is to determine how the Notch signaling pathway regulates the formation and growth of brain tumors, and to develop new brain tumor therapies based on Notch pathway inhibition. Notch receptors control the specification, proliferation and survival of stem and progenitor cells in the brain. Notch signaling is also implicated in tumorigenesis, including the formation and growth of brain tumors such as medulloblastoma and glioma. We have recently shown that the Notch2 gene is amplified and overexpressed in primary medulloblastoma/PNET, and promotes growth of medulloblastoma cell lines. In contrast, NotcM inhibits medulloblastoma cell proliferation. We are the first group to define an in vitro system in which two Notch receptors have opposing effects. We will create chimeras between Notch 1 and Notch2 and exploit this system to determine which domains of Notch differentially regulate proliferation and differentiation (Aim I). This should provide basic insights into the mechanism of Notch signaling, and also help guide our development of new therapies. To effectively treat brain tumors via Notch modulation, it will also be important to understand the mechanisms by which the pathway is turned on, as it must be blocked at or below the level of activation. In Aim II, we will therefore determine the roles of ligand stimulation and receptor mutation in activating the Notch pathway in medulloblastoma. A third aim is to assess the effects of Notch pathway blockade on tumor stems cells and tumor propagation. We have already shown that Notch pathway blockade inhibits proliferation and induces apoptosis of medulloblastoma in vitro. Recently, cells with stem- like properties have been isolated from freshly resected human medulloblastoma/PNET. This subset of neoplastic cells appears to be critical in propagating brain tumors, functioning as "tumor stem cells." Targeted therapies causing tumor stem cells to differentiate or die therefore represent a novel therapeutic avenue with great promise. We hypothesize that the Notch pathway, which controls neural stem cell survival and proliferation during normal fetal development, will also be required for tumor stem cells survival, and will test this in Aim III. Finally, it is not known if persistent activation of Nbtch2 is sufficient to initiate the formation of medulloblastoma. In Aim IV, we will introduce activated Notch2 into cerebellar precursor cells and assess its transforming capacity.

描述（申请人提供）：本提案的目标是确定Notch信号通路如何调节脑肿瘤的形成和生长，并开发基于Notch通路抑制的新脑肿瘤疗法。 Notch受体控制大脑中干细胞和祖细胞的规范、增殖和存活。 Notch信号传导还与肿瘤发生有关，包括髓母细胞瘤和神经胶质瘤等脑肿瘤的形成和生长。我们最近发现，Notch2 基因在原发性髓母细胞瘤/PNET 中扩增并过度表达，并促进髓母细胞瘤细胞系的生长。相反，NotcM 抑制髓母细胞瘤细胞增殖。我们是第一个定义体外系统的小组，其中两个Notch受体具有相反的作用。我们将在 Notch 1 和 Notch2 之间创建嵌合体，并利用该系统来确定 Notch 的哪些域差异调节增殖和分化（目标 I）。这将为Notch信号传导机制提供基本见解，并有助于指导我们新疗法的开发。为了通过Notch调制有效治疗脑肿瘤，了解该通路开启的机制也很重要，因为它必须在激活水平或低于激活水平被阻断。因此，在 Aim II 中，我们将确定配体刺激和受体突变在激活髓母细胞瘤中 Notch 通路中的作用。第三个目标是评估Notch通路阻断对肿瘤干细胞和肿瘤增殖的影响。我们已经证明，Notch 通路阻断可在体外抑制髓母细胞瘤的增殖并诱导其凋亡。最近，从新切除的人髓母细胞瘤/PNET 中分离出具有干细胞样特性的细胞。这种肿瘤细胞亚群似乎对脑肿瘤的增殖至关重要，发挥着“肿瘤干细胞”的作用。因此，导致肿瘤干细胞分化或死亡的靶向治疗代表了一种具有巨大前景的新型治疗途径。我们假设，在正常胎儿发育过程中控制神经干细胞存活和增殖的 Notch 通路也是肿瘤干细胞存活所必需的，并将在 Aim III 中对此进行测试。最后，尚不清楚 Nbtch2 的持续激活是否足以引发髓母细胞瘤的形成。在目标 IV 中，我们将把激活的 Notch2 引入小脑前体细胞并评估其转化能力。