The Role of GABA Transaminase ABAT in Pediatric Brain Tumor Medulloblastoma Development and Spread

GABA 转氨酶 ABAT 在小儿脑肿瘤髓母细胞瘤发展和扩散中的作用

• 批准号: 10716956
• 负责人: ANAT ERDREICH-EPSTEIN
• 金额: $ 57.96万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716956
• 关键词: 4-Aminobutyrate aminotransferase; ATAC-seq; Amino Acid Sequence; BARHL1 gene; Biological; Biological Assay; Blood - brain barrier anatomy; Brain; Cell Nucleus; Cells; Cerebellum; Cerebrospinal Fluid; Cessation of life; Characteristics; Child; Childhood Brain Neoplasm; Childhood Malignant Brain Tumor; Chromatin Structure; Cisplatin; Competence; Control Animal; Cytoplasmic Granules; Data; Development; Disease; Energy-Generating Resources; Enzymes; Epigenetic Process; Foundations; Gene Activation; Genetic Transcription; Goals; Growth; Histone Acetylation; Histone Deacetylase; Histone H3; Human; Immunoprecipitation; In Vitro; Leptomeninges; Lesion; Life; Lysine; Malignant Neoplasms; Maximum Tolerated Dose; Metabolic; Metabolism; Metastatic Neoplasm to the Leptomeninges; Mitochondria; Modification; Mus; Neoplasm Metastasis; Nervous System; Neurobiology; Neuroglia; Neurons; Neurosciences; Neurotransmitters; Nuclear; Nutrient; Oncogenes; Outcome; Paper; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Primary Neoplasm; Proliferating; Publishing; Receptor Activation; Reporting; Research; Role; Route; Shunt Device; Signal Transduction; Site; Spectrum Analysis; Therapeutic; Toxic effect; Transgenic Mice; Vincristine; Xenograft procedure; blood-brain barrier crossing; blood-brain barrier permeabilization; comparison control; gamma-Aminobutyric Acid; in vivo; induced pluripotent stem cell; inducible gene expression; inhibitor; knock-down; medulloblastoma; mortality; mouse model; neoplastic cell; nerve stem cell; neural; neurodevelopment; novel; novel therapeutic intervention; overexpression; protein H(3); radiation resistance; receptor; small molecule; standard of care; stem cell differentiation; therapeutic target; transcriptome; transcriptome sequencing; tumor; tumor microenvironment; tumorigenic

Medulloblastoma (MB), is the most common pediatric brain tumor originating in the GABA-rich cerebellum. 40% of MB patients present as both cerebellar and cerebral spinal fluid (CSF) leptomeningeal metastases which results in having dismal outcomes. The project’s long-term goal is to determine how MB become life-threatening leptomeningeal metastases by studying the tumor and brain microenvironment from a neurodevelopment and cancer neuroscience perspective. Although abnormal GABAergic receptor activation has been described in group 3 MB, no studies until ours recently had yet to elucidate the contribution of receptor-independent GABA metabolism to MB pathogenesis and metastasis. Overall, we were the first to identify GABA metabolic shunt enzyme GABA Transaminase (ABAT) expression is correlated with cerebellar development and is used by MB to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination. Specifically, we show proliferative MB cells at the primary cerebellar site have low ABAT. However, a sub-population of ABAT positive MB cells at the primary cerebellar site display neuron-like characteristics (including metabolism) and are the seeds of MB metastasis. In addition to being a GABA metabolic enzyme, we determined that expression of ABAT induces epigenetic modification by significantly reducing histone acetylation at the 4th lysine residue of the histone H3 protein (H3K4ac) and significantly increase in histone deacetylase activity. Furthermore, ABAT expression fluctuates depending on metabolite changes in the tumor microenvironment, with nutrient-poor conditions upregulating ABAT expression. We found metastatic MB cells require ABAT to maintain viability in the metabolite-scarce CSF by using GABA through the GABA metabolic shunt as an energy source substitute, thereby facilitating leptomeningeal metastasis formation. Therefore, we hypothesize ABAT has a dual-biological role: lack of its expression during normal cerebellar development contributes to proliferation leading to group 3 medulloblastoma formation; While its overexpression after MB development results in tumor dormancy leading to survival benefit in disseminated cells in leptomeningeal metastasis. Utilizing foundations of neurobiology by using: a) human and mouse-derived neural stem cells, neurons and glial cells, b) unique strengths of patient-xenografts, c) BarTeL transgenic mice, d) novel small molecule ABAT inhibitor which crosses the blood-brain barrier, we will: 1st interrogate the role of ABAT in cerebellar neurodevelopment and Group 3 MB initiation, 2nd contribution of nuclear ABAT to transcription through histone acetylation modification in metastases, 3rd investigate ABAT as a potential therapeutic target for MB metastases. The current proposal will shed further light on understanding how metastatic MB cells develop and adapt to their neural niche opening avenues for novel therapeutic interventions for children that have this devastating disease.

髓母细胞瘤（MB）是起源于富含GABA的小脑的最常见的小儿脑肿瘤。 MB的40％ 患者同时表现为小脑和脑脊髓液（CSF）瘦脑脑转移，这导致沮丧 结果。该项目的长期目标是确定MB如何通过威胁生命的瘦脑转移。 从神经发育和癌症神经科学的角度研究肿瘤和脑微环境。虽然 在第3组MB中已经描述了异常的GABA能受体激活，直到我们最近才有研究 为了阐明与接收者无关的GABA代谢对MB发病机理和转移的贡献。全面的， 我们是第一个识别GABA代谢分流酶Gaba Transamiase（ABAT）表达的人 小脑发育，并由MB用于脑脊液微环境中生存并促进 瘦脑传播。具体而言，我们在初级小脑部位显示增生剂MB细胞的ABAT较低。 但是，在小脑部位的ABAT阳性MB细胞的亚群显示出神经元的特征 （包括新陈代谢），是MB转移的种子。除了是GABA代谢酶外，我们确定了 ABAT的表达通过在第4个歌词下显着降低组蛋白乙酰化来诱导表观遗传修饰 组蛋白H3蛋白（H3K4AC）的残基，组蛋白脱乙酰基酶活性显着增加。此外，Abat 表达取决于肿瘤微环境的代谢物变化，并有营养贫困的条件 上调Abat表达。我们发现转移性MB细胞需要ABAT以维持代谢物降低的生存能力 通过通过GABA代谢分流为能源替代品，CSF通过使用GABA，从而支持瘦脑 转移形成。因此，我们假设ABAT具有双生物学作用：在正常情况下缺乏表达 小脑发育有助于增殖，从而导致第3组髓母细胞瘤形成。而它的 MB发育后的过表达导致肿瘤休眠，从而导致在传播细胞中的生存益处 瘦脑转移。利用神经生物学基础，使用：a）人类和小鼠衍生的神经元干细胞， 神经元和神经胶细胞，b）患者 - Xenograpts的独特强度，c）Bartel转基因小鼠，d）新型小分子添加 横穿血脑屏障的抑制剂，我们将：第一询问ABAT在小脑神经发育中的作用 和3组MB计划，通过组蛋白乙酰化修饰在转录中的第二贡献 转移，第三个研究ABAT是MB转移的潜在治疗靶标。当前的提议将进一步抛弃 了解转移性MB细胞如何发展并适应其神经利基开口途径 患有这种毁灭性疾病的儿童的治疗干预措施。