A causal role for asymmetric cell division defects in glioma initiation

不对称细胞分裂缺陷在神经胶质瘤发生中的因果作用

• 批准号: 8586853
• 负责人: Claudia Katharina Petritsch
• 金额: $ 31.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-13 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586853
• 关键词: Address; Adenoviruses; Adult; Alleles; Automobile Driving; Biological Assay; Brain; Brain Neoplasms; Breeding; CSPG4 gene; Cell Culture Techniques; Cell Separation; Cell division; Cells; Cessation of life; Chondroitin Sulfate Proteoglycan; Data; Defect; Drosophila polo protein; Embryo; Epidermal Growth Factor Receptor; Glioma; Goals; Growth; Health; Human; Image; Injection of therapeutic agent; Knockout Mice; LOX gene; Larva; Lead; Link; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Mediating; Mission; Mitosis; Modeling; Molecular; Mus; NG2 antigen; Neoplastic Cell Transformation; Oligodendroglia; Oligodendroglial Neoplasm; Patients; Proliferating; Proteins; Research; Role; Signal Transduction; Staging; Stem cells; Testing; Therapeutic; Time; Transgenic Organisms; cancer therapy; conventional therapy; daughter cell; epidermal growth factor receptor VIII; in vivo; inhibitor/antagonist; mouse model; mutant; nerve stem cell; novel; novel therapeutic intervention; oligodendroglioma; postnatal; prevent; progenitor; response; self-renewal; tumor; tumor growth; tumor initiation

DESCRIPTION (provided by applicant): Gliomas are the most common and deadly brain tumors in adults and can arise from mutant oligodendrocyte progenitors by a largely unknown mechanism. Specific treatments to eliminate these malignant OPC have not been developed, primarily because the underlying mechanisms associated with their malignant transformation are not well understood. The goal of this proposal is to find the underlying causes for malignant transformation of OPC by investigating defects in asymmetric cell division and to test specific pharmacological agents targeted to re-store these defects for their ability to impact tumor growth. We have recently provided first molecular evidence that oligodendrocyte progenitors divide asymmetrically to self-renew and generate mature oligodendrocytes by showing that the transmembrane proteoglycan NG2 distributes asymmetrically during mitosis and thereby promotes activation of epidermal receptor growth factor and self-renewal and prevents differentiation of the NG2+ progeny. Oligodendrocyte progenitors with defective NG2 asymmetry aberrantly self-renew, fail to differentiate and turn into glioma - initiating cells. We hypothesize that losing cellular asymmetry transforms oligodendrocyte progenitor cells, by disrupting self-renewal and differentiation. Our preliminary results indeed show that enforcing a block of asymmetric cell division by removing expression of conserved asymmetry regulator Lethal giant larvae, LGL1, in oligodendrocyte progenitors causes tumor formation. Moreover, pharmacological inhibition of Plk1, a conserved regulator of asymmetric cell division, re-stores NG2 asymmetry in malignant, glioma- initiating cells. Guided by such strong preliminary data, we have three specific aims: In the first aim, we determine whether oligodendrocyte progenitor-specific loss of LGL1 causes NG2-dependent tumor- initiation. To fulfill this aim, we propose to generate oligodendrocyte progenitors and oligodendrocyte progenitor precursor deficient for LGL1 alone and co-deficient for LGL1 and NG2, in mouse models using a CRE-LOX approach. The analysis of tumor formation in these models will enable us to distinguish between NG2-dependent and - independent functions of LGL1 in tumor initiation. In the second aim, we will determine a causal link of loss of LGL1, disrupted NG2 asymmetry and tumor initiation in OPC. We will test LGL1-/- oligodendrocyte progenitors for defects in NG2 asymmetry, self-renewal and differentiation. To link losing LGL1 and NG2 asymmetry to malignant transformation, we will evaluate the malignant potential of LGL1-/- and test whether co-deletion of NG2 ameliorates tumor formation and re-expression of symmetric, ectopic NG2 enhances defects in LGL1-/- OPC. In the third aim, we will investigate the pharmacological modulation of asymmetric cell division for its impact on tumor growth. Our goal is to prove that loss of asymmetric cell division is causal to tumor initiation and thereby evaluate novel therapeutic approaches that re-store asymmetric cell division to malignant progenitors and for their potential to impact tumor growth.

描述（由申请人提供）：胶质瘤是成人中最常见和最致命的脑肿瘤，可以通过很大程度上未知的机制由突变的少突胶质细胞祖细胞引起。尚未开发消除这些恶性OPC的特定治疗方法，主要是因为与其恶性转化相关的潜在机制尚未得到充分理解。该提案的目标是通过研究不对称细胞分裂的缺陷来找到OPC恶性转化的根本原因，并测试针对恢复这些缺陷的特定药理学试剂，以确定其影响肿瘤生长的能力。我们最近提供了第一个分子证据，证明少突胶质细胞祖细胞不对称分裂以自我更新并产生成熟的少突胶质细胞，表明跨膜蛋白聚糖NG 2在有丝分裂期间不对称分布，从而促进表皮受体生长因子的激活和自我更新，并防止分化NG 2+后代。NG 2不对称缺陷的少突胶质细胞祖细胞异常自我更新，不能分化并转化为胶质瘤起始细胞。我们假设，失去细胞的不对称性转化少突胶质细胞祖细胞，破坏自我更新和分化。我们的初步研究结果确实表明，通过去除少突胶质祖细胞中保守的不对称调节因子LGL 1的表达来阻断不对称细胞分裂会导致肿瘤形成。此外，药理学抑制Plk 1，一种保守的不对称细胞分裂调节剂，恢复了恶性胶质瘤起始细胞中的NG 2不对称性。在这样强有力的初步数据的指导下，我们有三个具体的目标：在第一个目标中，我们确定LGL 1的少突胶质细胞祖细胞特异性缺失是否导致NG 2依赖性肿瘤起始。为了实现这一目标，我们提出使用CRE-LOX方法在小鼠模型中产生单独缺乏LGL 1和共同缺乏LGL 1和NG 2的少突胶质细胞祖细胞和少突胶质细胞祖细胞前体。在这些模型中的肿瘤形成的分析将使我们能够区分NG 2依赖性和非依赖性的LGL 1在肿瘤起始的功能。在第二个目标中，我们将确定OPC中LGL 1丢失、NG 2不对称性破坏和肿瘤起始的因果关系。我们将测试LGL 1-/-少突胶质细胞祖细胞在NG 2不对称性、自我更新和分化方面的缺陷。为了将失去LGL 1和NG 2不对称性与恶性转化联系起来，我们将评估LGL 1-/-的恶性潜能，并测试NG 2的共缺失是否改善肿瘤形成，以及对称的异位NG 2的再表达是否增强LGL 1-/- OPC中的缺陷。在第三个目标中，我们将研究不对称细胞分裂的药理学调节对肿瘤生长的影响。我们的目标是证明不对称细胞分裂的丧失是肿瘤发生的原因，从而评估将不对称细胞分裂恢复为恶性祖细胞的新治疗方法及其影响肿瘤生长的潜力。