Diverse roles of Notch signaling in glioblastoma

Notch 信号在胶质母细胞瘤中的多种作用

基本信息

批准号：
8686298
负责人：
Dimitris G. Placantonakis
金额：
$ 16.72万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686298
关键词：
Address Aftercare Alkylating Agents Animals Applications Grants Area Attenuated Biology Brain Brain Neoplasms Caring Cell Fraction Cell Lineage Cell physiology Cell surface Cells Clinical Management Data Development Disease Funding Funding Opportunities Genetic Genetic Engineering Glioblastoma Growth Heterogeneity Human Hurricane Image In Vitro Laboratories Lead Light Magnetic Resonance Imaging Malignant Neoplasms Modeling Molecular Mus Notch Signaling Pathway Pathway interactions Primary Brain Neoplasms Property Publications Recovery Recurrence Reporter Research Resistance Role Series Shapes Signal Transduction Specimen System Techniques Testing Therapeutic Time Work Xenograft Model Xenograft procedure animal facility chemoradiation chemotherapeutic agent chemotherapy conventional therapy design in vivo molecular marker neoplastic cell neuro-oncology notch protein novel novel therapeutic intervention outcome forecast public health relevance research study response self-renewal stem stem cells therapeutic target therapy development tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is an incurable brain malignancy with limited treatment options. Within GBM, cells with stem-like properties (GBM stem cells or GSCs) initiate and propagate tumors, and are highly resistant to conventional chemoradiotherapy. A major obstacle in understanding the biology of GSCs and developing therapies that directly target them has been the lack of molecular markers that universally identify them. Previous observations indicated that inhibition of Notch signaling, a pathway that regulates fate decisions in neuroglial development, attenuates but does not completely block the self-renewal of GSCs. These findings raise the possibility that Notch activation may be critical to some but not all GSCs, suggesting functional and molecular heterogeneity within the GSC compartment. Prior to Hurricane Sandy, we initiated a set of experiments aiming to clarify the identity of GBM cells in which Notch signaling is activated and understand their contribution to tumor heterogeneity during tumor growth and in response to chemotherapy. Using primary human GBM cultures genetically engineered to express fluorescent reporters in response to activation of Notch signaling, we discovered that, under in vitro conditions that favor GSC self-renewal, Notch is activated in cells that do not express CD133, a well-established cell surface marker of GSCs. Furthermore, we found that in vitro induction of differentiation increases the fraction of cells with activated Notch signaling. These findings raise important questions about the role of the Notch pathway in the cellular hierarchy of GBM: Does Notch signaling identify stem cells with tumor initiating properties or a different type of progenitor cells within GBM? What are the lineages that descend from cells in which Notch signaling is active in vivo? And how do these cells respond to chemotherapy treatment? Unfortunately, the storm inflicted substantial damage to our laboratory, including loss of our primary human GBM cultures. In addition, we had to re-establish our mouse colony in a new animal facility within NYU. Through this funding opportunity, we are requesting funds to extend our preliminary work to further understand the function on the Notch pathway in GBM. Our experiments will assess whether cells with active Notch signaling have tumor- initiating properties and what cell lineages they generate in vivo, including after treatment with the chemotherapeutic agent temozolamide, a mainstay in clinical management of GBM. We anticipate that our findings will generate a critical mass of data that will lead to a publication and a successful submission of an R01 proposal. Importantly, our findings will shed light on an important area of research within neuro-oncology and will facilitate the design of novel and informed therapeutic strategies.

描述（由申请人提供）：多形胶质母细胞瘤（GBM）是一种无法治愈的脑恶性肿瘤，治疗方案有限。在GBM中，具有茎状特性（GBM干细胞或GSC）的细胞启动并传播肿瘤，并且对常规的化学放疗具有高度耐药性。理解GSC的生物学和开发直接针对它们的疗法的主要障碍是缺乏普遍识别它们的分子标记。先前的观察结果表明，抑制Notch信号传导，这是一种调节神经乳头发育中命运决定的途径，减弱但不能完全阻止GSC的自我更新。这些发现提出了可能对Notch激活至关重要的可能性一些但不是全部GSC，表明GSC室内的功能和分子异质性。在飓风桑迪之前，我们启动了一系列实验，目的是阐明GBM细胞的身份，其中notch信号被激活，并了解它们在肿瘤生长过程中对肿瘤异质性的贡献以及对化学疗法的反应。使用基因设计的原代人GBM培养物以响应Notch信号的激活来表达荧光记者，我们发现，在有利于GSC自我更新的体外条件下，Notch在不表达CD133的细胞中激活，该细胞是GSC的良好细胞表面标记。此外，我们发现通过激活的Notch信号传导，分化的体外诱导会增加细胞的比例。这些发现提出了有关Notch途径在GBM细胞层次结构中的作用的重要问题：Notch信号传导是否识别出具有肿瘤启动性质或GBM内不同类型的祖细胞的干细胞？从体内活性的细胞中降下的谱系是什么？这些细胞如何应对化疗治疗？不幸的是，这场风暴对我们的实验室造成了重大破坏，包括失去人类GBM文化。此外，我们不得不在纽约大学的新动物设施中重新建立老鼠菌落。通过这个资金机会，我们要求资金扩展我们的初步工作，以进一步了解GBM中Notch途径的功能。我们的实验将评估具有活性Notch信号传导的细胞是否具有肿瘤的特性以及它们在体内产生的细胞谱系，包括用化学治疗剂Temozolamide治疗后，这是GBM临床管理中的中流型。我们预计我们的发现将产生大量数据，这将导致出版物和成功提交R01提案。重要的是，我们的发现将阐明神经肿瘤学内的重要研究领域，并将促进新颖和知情的治疗策略的设计。