Hedgehog:YAP:IGF2/mTOR axis in cerebellar precursor division and medulloblastoma

Hedgehog:YAP:IGF2/mTOR 轴在小脑前体分裂和髓母细胞瘤中的作用

• 批准号: 8384285
• 负责人: Anna Marie Kenney
• 金额: $ 9.36万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384285
• 关键词: Ablation; Adverse effects; Affect; Binding; Biological; Brain; Cell Cycle Progression; Cell Nucleus; Cell Survival; Cells; Cephalic; Cerebellum; Cerebrospinal Fluid; Child; Childhood; Collaborations; Cytoplasmic Granules; DNA Damage; DNA Repair; Development; Engineering; Erinaceidae; Eukaryotic Initiation Factor-4E; Event; Gene Expression Profile; Gene Proteins; Genes; Genetic; Genetic Translation; Genetically Engineered Mouse; Genomic Instability; Goals; Grant; Growth; Home environment; Human; Hypoxia Inducible Factor; IGF2 gene; Impaired cognition; In Vitro; Incidence; Lead; Left; Life; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Metastatic malignant neoplasm to brain; Modality; Molecular; Molecular Target; Mus; Neonatal; Neoplasm Metastasis; Neurons; Oncogenes; Oncogenic; Operative Surgical Procedures; Pathway interactions; Patients; Play; Predisposition; Premature aging syndrome; Process; Production; Proliferating; Proteins; Publications; Quality of life; Radiation; Recurrence; Regulation; Reporting; Retroviridae; Role; Sampling; Seizures; Signal Pathway; Signal Transduction; Solid; Somatomedins; Sonic Hedgehog Pathway; Spinal; Stem cells; Survivors; System; Testing; Therapeutic; Translations; Up-Regulation; Ursidae Family; chemotherapy; human FRAP1 protein; hypoxia inducible factor 1; implantation; improved; in vivo; insight; insulin receptor substrate 1 protein; knock-down; medulloblastoma; mortality; mouse model; neoplastic cell; nerve stem cell; novel; precursor cell; protein expression; radiation resistance; response; standard of care; therapeutic target; transcription factor; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Medulloblastomas are the most common solid pediatric malignant tumors. These tumors arise in young children from dividing progenitor cells in the cerebellum. Current treatments for medulloblastoma, surgery, cranio-spinal radiation, and chemotherapy, leave survivors with life-long, devastating side effects. Moreover, medulloblastoma recurrence and metastasis are lethal. Development of new medulloblastoma therapies that are less debilitating and more effective has been hampered by poor understanding of the molecular and cell biological events causing the tumors and promoting their recurrence and metastasis. Greater insight into how genes and proteins regulate proliferation in cerebellar progenitor cells, and how their dys-regulation contributes to tumorigenesis, will identify targets for new therapies that can specifically affect tumor growth without damaging the still-developing brain. Medulloblastomas are divided into 4-6 genetic subclasses. Approximately 30% of medulloblastomas are associated with a Sonic hedgehog (SHH) pathway genetic signature, and aberrant activation of this pathway promotes medulloblastoma in genetically engineered mouse models. Cerebellar granule neuron precursors (CGNPs) have been proposed as cells of origin for SHH medulloblastomas, and they depend on SHH for proliferation during development. In vitro, these cells (derived from neonatal mice) divide and differentiate much as they do in vivo, hence they are useful for studying how signaling pathways regulate proliferation during normal brain development and in medulloblastomas. Using such cultures and mouse models, we have found that Shh promotes activity of the oncogene YAP, which in turn drives expression of IGF2, contributing to enhanced proliferation and permitting tumor cells to survive radiation, which can lead to tumor recurrence and genomic instability. Importantly, we have shown that YAP and IGF2 are highly expressed in human SHH medulloblastomas. The studies described in the proposal "Hedgehog:YAP:IGF2/mTOR axis in cerebellar precursor division and medulloblastoma" focus on characterizing how these pathways interact to promote medulloblastoma growth and metastasis. These studies use primary CGNP cultures, analysis of wild-type and Shh medulloblastoma-bearing mice, and anonymized human patient samples to investigate how YAP regulates IGF2, whether IGF2 inhibition may be a viable therapeutic modality, determine the requirement for YAP in Shh medulloblastoma growth, recurrence, and metastasis, and test the hypothesis that hypoxia-inducible factor (HIF) lies downstream of Shh/IGF-mediated mTOR activation and plays critical roles in Shh mitogenic and oncogenic signaling. The long-term goal of these studies is to determine how modulating the function of Shh and IGF downstream effectors such as YAP and HIF might be a useful therapeutic approach to treat medulloblastomas and other cancers where these pathways are active. PUBLIC HEALTH RELEVANCE: Medulloblastomas, the most common solid malignant pediatric tumor, arise in the developing brain of young children. These tumors are currently treated with surgery, cranio-spinal radiation, and chemotherapy. Survivors suffer devastating life-long side effects due to the damage these treatments do to the still developing brain, and metastasis and recurrence are lethal. The studies proposed in "Hedgehog:YAP:IGF2/mTOR axis in cerebellar precursor division and medulloblastoma" will investigate how molecules that promote proliferation and survival in the developing brain contribute to medulloblastoma formation, recurrence, and metastasis, and will test the hypothesis that such molecules are potential targets for therapeutic approaches that will be less harmful to patients.

描述（由申请人提供）：髓母细胞瘤是最常见的儿科实体恶性肿瘤。这些肿瘤发生在幼儿中，由小脑中分裂的祖细胞产生。目前髓母细胞瘤的治疗方法、手术、颅脊髓放疗和化疗给幸存者留下了终生的、毁灭性的副作用。而且，髓母细胞瘤的复发和转移是致命的。由于对引起肿瘤并促进其复发和转移的分子和细胞生物学事件了解不足，阻碍了新的髓母细胞瘤疗法的开发，这种疗法的衰弱程度更小，更有效。更深入地了解基因和蛋白质如何调节小脑祖细胞的增殖，以及它们的失调如何导致肿瘤发生，将确定新疗法的靶点，这些疗法可以专门影响肿瘤生长，而不损害仍在发育的大脑。 髓母细胞瘤分为 4-6 个遗传亚类。大约 30% 的髓母细胞瘤与音刺猬 (SHH) 通路遗传特征相关，该通路的异常激活会在基因工程小鼠模型中促进髓母细胞瘤的发生。小脑颗粒神经元前体 (CGNP) 被认为是 SHH 髓母细胞瘤的起源细胞，它们在发育过程中依赖于 SHH 进行增殖。在体外，这些细胞（来自新生小鼠）的分裂和分化与体内的情况非常相似，因此它们可用于研究信号通路如何在正常大脑发育和髓母细胞瘤中调节增殖。使用此类培养物和小鼠模型，我们发现Shh促进癌基因YAP的活性，进而驱动IGF2的表达，有助于增强增殖并允许肿瘤细胞在辐射中存活，从而导致肿瘤复发和基因组不稳定。重要的是，我们已经证明 YAP 和 IGF2 在人 SHH 髓母细胞瘤中高表达。 “Hedgehog:YAP:IGF2/mTOR 轴在小脑前体分裂和髓母细胞瘤中的作用”提案中描述的研究重点是描述这些通路如何相互作用以促进髓母细胞瘤的生长和转移。这些研究使用原代 CGNP 培养物、对野生型和 Shh 髓母细胞瘤小鼠的分析以及匿名人类患者样本来研究 YAP 如何调节 IGF2、IGF2 抑制是否可能是一种可行的治疗方式，确定 Shh 髓母细胞瘤生长、复发和转移中对 YAP 的需求，并检验缺氧诱导因子的假设 (HIF) 位于 Shh/IGF 介导的 mTOR 激活下游，在 Shh 有丝分裂和致癌信号传导中发挥关键作用。这些研究的长期目标是确定调节 Shh 和 IGF 下游效应器（例如 YAP 和 HIF）的功能如何成为治疗髓母细胞瘤和这些通路活跃的其他癌症的有用治疗方法。 公共卫生相关性：髓母细胞瘤是最常见的儿童实体恶性肿瘤，出现在幼儿发育中的大脑中。这些肿瘤目前通过手术、颅脊髓放疗和化疗进行治疗。 由于这些治疗对仍在发育的大脑造成的损害，幸存者会遭受毁灭性的​​终生副作用，而且转移和复发是致命的。 “小脑前体分裂和髓母细胞瘤中的刺猬：YAP：IGF2/mTOR轴”中提出的研究将研究促进发育中大脑增殖和存活的分子如何促进髓母细胞瘤的形成、复发和转移，并将检验这样的假设：这些分子是对患者危害较小的治疗方法的潜在靶标。