Specialized Niches for Pediatric Astrocytoma Cells

儿童星形细胞瘤细胞的专门利基

• 批准号: 8376549
• 负责人: ROSALIND A. SEGAL
• 金额: $ 35.36万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8376549
• 关键词: Adenylate Cyclase; Antibodies; Area; Astrocytoma; BRAF gene; Biological Assay; Brain; Brain Stem; Brain region; Cell Survival; Cells; Cerebellar Astrocytoma; Cerebellar Pilocytic Astrocytoma; Cerebellum; Characteristics; Child; Childhood Astrocytic Tumor; Childhood Brain Neoplasm; Cilia; Environment; Event; Exhibits; Future; Growth; Human; Instruction; Location; Maintenance; Mutation; Oncogenic; Organelles; Pathology; Pathway interactions; Patients; Prosencephalon; Sampling; Signal Transduction; Slice; Specificity; Specimen; Therapeutic; Treatment Efficacy; Tubulin; Xenograft procedure; base; hindbrain; innovation; migration; neoplastic cell; nerve stem cell; new therapeutic target; novel therapeutic intervention; overexpression; response; tumor; tumor growth

The overall objective ofthis project is to develop a new understanding ofthe microenvironment that supports the growth, survival and migration of astrocytoma cells, and thereby identify new therapeutic approaches. In preliminary studies we have shown that human astrocytoma cells do not grow indiscriminately within the brain parenchyma, but prefer to grow in particular microenvironments. In the proposed studies we will use primary cultures from patient samples to determine whether astrocytomas are addicted to the environment of the brain region in which they developed, and to define cellular mechanisms by which the tumor microenvironment promotes tumor maintenance. We have three aims: Aim One: Determine whether pediatric astrocytomas are "addicted" to the particular location in which they originated. We will use a new slice overiay assay, to determine whether i) forebrain tumors preferenfially grow in the specialized microenvironment of the forebrain; ii) hindbrain tumors preferentially grow in the cerebellum and brainstem areas ofthe hindbrain; iii) BRAF overexpression, a characteristic feature of cerebellar pilocytic astrocytomas, specifically facilitates growth of neural precursor in the cerebellar microenvironment. Aim Two: Define the cellular basis ofthe microenvironment While the microenvironment is cleariy important for tumor growth and maintenance, the reason why tumor cells are preferentially found in particular locations is not understood. We will determine whether i) the microenvironment stimulates tumor proliferafion; ii) the microenvironment selectively promotes tumor cell survival; iii) tumor cells preferentially migrate towards this microenvironment. Aim Three: Determine whether primary cilia coordinate the tumor cell response to its microenvironment. Our preliminary studies indicate that many astrocytoma samples exhibit primary cilia, visualized with antibodies to acetylated tubulin or adenylate cyclase 3. To determine whether primary cilia are signaling organelles that contribute to growth of astrocytomas, we will determine whether i) Primary cilia are preferenfially found on higher grade tumors; ii) Primary cilia point towards the vasculature; iii) components of crifical growth pathways localized to cilia of tumor cells; iv) Primary cilia are required for tumor growth. RELEVANCE (See instructions): In cooperation with the Innovative Neuro Pathology (INP) Core and Projects One and Two, these studies on the tumor microenvironment will identify new therapeutic targets for treating pediatric brain tumors. Future therapies can then be developed that attack the interactions of the tumor and its microenvironment, an approach that may allow therapeutic efficacy with less damage to the normally developing brains of children. J PROJECT/

该项目的总体目的是对支持的微环境有了新的了解 星形细胞瘤细胞的生长，存活和迁移，从而确定了新的治疗方法。在 初步研究我们已经表明，人类星形细胞瘤细胞不会在 脑实质，但更喜欢在特别环境中生长。在拟议的研究中，我们将使用 来自患者样本的初级培养物以确定星形胶质细胞是否会上瘾 他们开发的大脑区域，并定义肿瘤的细胞机制 微环境可促进肿瘤维持。我们有三个目标： 目标一个：确定小儿星形胶质细胞瘤是否在特定位置“上瘾” 他们起源。我们将使用新的切片过度测定法，以确定i）前脑肿瘤是否 在前脑的专业微环境中偏爱生长； ii）优先考虑后脑肿瘤 在后脑的小脑和脑干地区生长； iii）BRAF过表达，一个特征 小脑毛囊星形胶质细胞的特征，特异性促进了小脑神经前体的生长 微环境。 目标两个：在微环境中定义微环境的细胞基础 对于肿瘤的生长和维持至关重要，这是特别发现肿瘤细胞的原因 位置不了解。我们将确定i）微环境是否刺激肿瘤 扩散; ii）微环境有选择地促进肿瘤细胞的存活； iii）优先 向这种微环境迁移。 目标三：确定原发性纤毛是否协调肿瘤细胞对其肿瘤的反应 微环境。我们的初步研究表明，许多星形细胞瘤样品表现出原发性纤毛， 用乙酰化小管蛋白或腺苷酸环化酶3的抗体可视化。 是有助于星形胶质细胞瘤增长的信号细胞器，我们将确定是否） 在高级肿瘤上偏爱发现； ii）原发性纤毛指向脉管系统； iii） 定位于肿瘤细胞纤毛的分量生长途径的成分； iv）主要纤毛需要 肿瘤生长。 相关性（请参阅说明）： 与创新的神经病理学（INP）核心和一项项目合作，这些研究 在肿瘤上，微环境将确定用于治疗小儿脑肿瘤的新治疗靶点。未来 然后可以开发疗法，以攻击肿瘤及其微环境的相互作用， 可以允许治疗功效的方法，对正常发育的儿童大脑的损害较小。 j 项目/