Investigating ASPM regulation of asymmetric division for therapeutic opportunities

研究 ASPM 对不对称分裂的调节以获得治疗机会

• 批准号: 9355055
• 负责人: Claudia Katharina Petritsch
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355055
• 关键词: ASPM gene; Address; Astrocytoma; Binding; Biological Process; Brain Neoplasms; CSPG4 gene; Cell division; Cells; Cessation of life; Data; Down-Regulation; Drosophila genus; Drosophila polo protein; Dynein ATPase; Embryo; Ensure; Epidermal Growth Factor Receptor; Epigenetic Process; FOXO1A gene; Fishes; Gene Expression; Genetic; Glioblastoma; Glioma; Gliomagenesis; Goals; Growth; Health; Human; In Vitro; Malignant - descriptor; Malignant Neoplasms; Mediating; Microcephaly; Microtubules; Mission; Mitotic spindle; Molecular; Motor; Mus; Mutation; Neoplastic Cell Transformation; Neuroepithelial Cells; PIK3CG gene; Patients; Pharmacology; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor alpha Receptor; Positioning Attribute; Predisposition; Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogenes; RNA Interference; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Repression; Research; Role; Signal Transduction; Stem cells; Testing; Therapeutic; Time; Transcript; Transgenic Mice; United States National Institutes of Health; Up-Regulation; Viral; cancer therapy; constitutive active receptor; dynactin; experimental study; forkhead protein; improved; mRNA Expression; mouse model; neuroblast; new therapeutic target; novel therapeutic intervention; novel therapeutics; oligodendrocyte progenitor; oligodendroglioma; outcome forecast; progenitor; promoter; protein expression; self-renewal; small hairpin RNA; transcription factor; tumor; tumor growth; tumorigenesis

PROJECT SUMMARY/ABSTRACT Novel therapeutic approaches are desperately needed to improve the prognosis for glioma patients. Developing such approaches will require the delineation of key regulatory networks specific to glioma cells and leading to neoplastic transformation and enabling tumor growth. Past studies in mouse models identified oligodendrocyte progenitor cells (OPC) as putative cellular origin of astrocytoma and oligodendroglioma. Data from our lab showed that the switch from asymmetric, self-sustaining to symmetric, self-renewing divisions is a critical step in the neoplastic transformation of OPC. Therapies specifically interfering with aberrant symmetric cell divisions are expected to eliminate malignant OPCs and disrupt tumor growth. It is our long-term goal to develop such therapies, by defining the effect of glioma- associated genetic alterations on the asymmetric-to-symmetric cell division mode switch. The objective of this proposal is to test the hypothesis that abnormal spindle microcephaly associated Aspm mRNA expression is upregulated in glioma cells by constitutive-active receptor tyrosine kinase signaling via PI3K- AKT. We further propose that Aspm protein positively regulates symmetric divisions and thereby promotes neoplastic transformation and malignant growth. Functionally, Aspm positively regulates mitotic spindle integrity and positioning. We will achieve our objective by pursuing two independent aims. In Aim 1, we propose to identify the molecular switch from asymmetric to symmetric division in OPC, by determining if activation of the PDGFRα/EGFR-PI3K-AKT axis directly elevates Aspm transcript levels and thereby positively regulates symmetric cell division mode and increases proliferation rate. We expect that upon completion of these experiments, we will for the first time have demonstrated that the switch of cell division mode is regulated by an extrinsic signal through modulation of Aspm levels. In Aim 2. we will validate Aspm as a proto-oncogene and Aspm functions as therapeutic opportunities. We will suppress Aspm expression using RNAi in a selected panel of glioma cells with constitutively active PDGFRα or EGFR signaling. We anticipate that Aspm suppression will cause glioma cells to favor asymmetric divisions, which will decrease their proliferation rate and reduce their malignant potential. We anticipate that Aspm spindle regulatory functions provide novel therapeutic vulnerabilities in glioma cells. These studies can delineate a paradigm for enforcing symmetric cell division and tumorigenesis in all progenitor-driven tumors. By unraveling Aspm upregulation as a specific step in the neoplastic transformation of progenitor cells we identify a point of susceptibility for cancer therapies and provide a treatment paradigm for other progenitor-derived cancers.

项目摘要/摘要 迫切需要新型的热方法来改善神经胶质瘤患者的预后。 开发这种方法将需要描述特定于神经胶质瘤细胞的关键调节网络 并导致肿瘤转化并实现肿瘤生长。老鼠模型的过去研究 确定的少突胶质细胞祖细胞（OPC）是星形胶质细胞瘤和 少突胶质瘤。我们实验室的数据显示，从不对称，自我维持到 对称，自我更新分裂是OPC肿瘤转化的关键步骤。疗法 特别干扰异常的对称细胞分裂有望消除恶性OPC和 破坏肿瘤的生长。通过定义神经胶质瘤的作用，我们的长期目标是开发此类疗法 不对称到对称细胞分裂模式开关上的相关遗传改变。目的 该提议是测试异常纺锤体小头畸形与ASPM mRNA相关的假设 通过PI3K-的组成型活性受体酪氨酸激酶信号传导在神经胶质瘤细胞中进行表达。 akt。我们进一步提出，ASPM蛋白会积极调节对称分裂，从而促进 肿瘤转化和恶性生长。在功能上，ASPM积极调节有丝分裂主轴 诚信和定位。我们将通过追求两个独立目标来实现我们的目标。在AIM 1中，我们 提案以确定从OPC中从不对称到对称分裂的分子转换， 确定PDGFRα/EGFR-PI3K-AKT轴的激活是否直接提高ASPM转录水平和 从而积极调节对称细胞分裂模式并提高增殖率。我们期望这一点 这些实验完成后，我们将首次证明单元的转换 通过调节ASPM级别，通过外部信号调节除法模式。在AIM 2中。我们将 将ASPM验证为原始癌基因和ASPM作为治疗机会。我们将 在选定的胶质瘤细胞中使用RNAI抑制ASPM表达 PDGFRα或EGFR信号传导。我们预计ASPM抑制会导致神经胶质瘤细胞有利 不对称分裂将降低其增殖率并降低其恶性潜力。我们 预计ASPM纺锤体调节功能在神经胶质瘤细胞中提供了新的治疗脆弱性。 这些研究可以描绘出用于对称对称细胞分裂的范式和所有的肿瘤发生 祖细胞驱动的肿瘤。通过将ASPM上调作为肿瘤的特定步骤 祖细胞的转化我们确定了对癌症疗法的敏感性的点，并提供了 其他祖细胞衍生的癌症的治疗范式。