The hypoxic niche in glioblastoma is maintained by myeloid produced creatine

胶质母细胞瘤中的缺氧生态位由骨髓产生的肌酸维持

• 批准号: 10638880
• 负责人: Jason Miska
• 金额: $ 37.18万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638880
• 关键词: Ablation; Adult; Anabolism; Antitumor Response; Biological; Blood - brain barrier anatomy; Blood Vessels; Blood coagulation; Brain Neoplasms; Cell Hypoxia; Cell Separation; Cell Survival; Cells; Cellular Structures; Central Nervous System; Chemicals; Chemoresistance; Chemotherapy and/or radiation; Communication; Creatine; Data; Disease; Disease Progression; Environment; Enzymes; Event; Exhibits; Generations; Genes; Genetic; Genetic Models; Glioblastoma; Glioma; Glycine; Growth; Histologic; Histopathology; Human; Hyperplasia; Hypoxia; Infiltration; Lesion; Maintenance; Malignant Neoplasms; Metabolic; Metabolic stress; Metabolism; Modality; Modeling; Mus; Myelogenous; Myeloid Cells; Necrosis; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Primary Brain Neoplasms; Primary Neoplasm; Production; Pseudopalisading Necrosis; Radiation therapy; Recurrence; Research; Resistance; Role; Sampling; Source; Stress; Structure; Testing; Therapeutic; Therapeutic Intervention; Thrombosis; Tropism; Tumor Markers; Tumor Promotion; Tumor Tissue; Work; chemotherapy; clinical application; clinical development; clinically relevant; creatine transporter; experimental study; extracellular; fitness; human model; immune cell infiltrate; inhibitor; metabolic phenotype; mouse model; multiple omics; neoplastic cell; patient derived xenograft model; patient screening; pharmacologic; radiation resistance; single-cell RNA sequencing; stem cell biology; stem cells; stem-like cell; therapy resistant; transcriptomics; treatment strategy; tumor; tumor growth; tumor hypoxia; tumor microenvironment; tumor progression; uptake

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is the most common brain tumor malignancy in adults that is characterized by unique niches termed pseudo-palisading necrosis. These hypoxic regions are a defining feature of the disease which promote chemoresistance, radioresistance, and ultimately drive disease progression. Understanding the generation and sustainment of these regions is critical to understanding how to effectively treat the disease. Multi-omics analysis of human GBM patients reveals that the creatine transporter, Slc6a8 is specifically expressed by tumor cells in hypoxic and necrotic regions. Surrounding these regions are tumor-associated myeloid cells (TAMCs), which are the most abundant infiltrating immune cell in GBM. Surprisingly, the TAMCs that surround the hypoxic pseudo-palisading regions express the enzymes necessary to produce creatine. Therefore, we hypothesize that TAMC-derived creatine promotes the generation of the pseudo-palisading necrotic niche in GBM, and that this metabolic crosstalk promotes both GBM fitness and therapy resistance. Previous work has identified that the hypoxic pseudo-palisading niche contains glioma stem cells (GSC), which are generated by the hypoxic stress within these regions. Furthermore, Slc6a8 is directly regulated by hypoxia, suggesting creatine uptake exerts a role on GSC phenotypes. Thus, the first aim of this proposal is to examine how creatine transport influences GSC phenotypes in both human and mouse models of GBM. In this aim, we will also utilize inducible models of GBM that recapitulate the genetic and pathologic features of human GBM to determine if Slc6a8 is necessary for the formation of the hypoxic pseudo-palisading niche in tumors. Our preliminary data indicate that TAMCs isolated from both mice and humans with GBM are proficient producers of creatine. Furthermore, we found that this metabolic phenotype is specific to the tumor microenvironment (TME) and is induced by extracellular lactate. Thus, the second aim of this proposal will examine how the ablation of creatine biosynthesis by TAMCs controls tumor growth and progression in mouse models of GBM. This aim will also determine how lactate induces the creatine biosynthetic phenotype of TAMCs in GBM. The third aim of this proposal is to examine if a clinically relevant inhibitor of creatine transport influences GBM growth. We will test how this inhibitor works in the context of chemo and radiotherapy to determine how creatine uptake influences GBM recurrence. To establish translatable value from this work, we will generate tumor samples and patient-derived xenografts from patients, screen them for expression of creatine metabolic genes, then assess sensitivity to creatine metabolic inhibitory therapy. The results of this aim will identify if blocking TAMC-to-tumor metabolic communication is a feasible strategy for GBM therapy.

项目摘要/摘要 摘要胶质母细胞瘤是成人最常见的脑肿瘤，具有独特的特点。 被称为假栅栏坏死的壁龛。这些缺氧区是该病的一个明显特征， 促进化疗和辐射抵抗，并最终推动疾病进展。了解 这些区域的产生和维持对于了解如何有效治疗这种疾病至关重要。 对人GBM患者的多组学分析表明，肌酸转运蛋白SLC6a8是特异性的 在缺氧区和坏死区的肿瘤细胞表达。围绕这些区域的是与肿瘤相关的 髓样细胞(TAMCs)是GBM中含量最丰富的浸润性免疫细胞。令人惊讶的是，TAMC 围绕低氧假栅栏区域的蛋白表达产生肌酸所必需的酶。 因此，我们假设TAMC来源的肌酸促进了伪栅栏的产生 这种代谢串扰促进了基底膜的健康和治疗耐药。 以前的工作已经确定，低氧的假栅栏壁龛含有胶质瘤干细胞(GSC)， 它们是由这些区域内的低氧应激产生的。此外，SLC6a8直接由 低氧，提示肌酸摄取对GSC表型起作用。因此，这项提议的第一个目标是 研究肌酸转运如何影响人类和小鼠GBM模型中的GSC表型。在这 目的，我们还将利用可诱导的基底膜模型来概括人类的遗传和病理特征。 确定SLC6a8是否对肿瘤中低氧假栅栏生态位的形成是必需的。 我们的初步数据表明，从患有GBM的小鼠和人身上分离的TAMCs是熟练的 肌酸的生产商。此外，我们发现这种代谢表型是肿瘤特有的。 微环境(TME)，并由胞外乳酸诱导。因此，这项提案的第二个目标将是 研究TAMCs对肌酸生物合成的抑制作用如何控制小鼠肿瘤的生长和发展 GBM的模型。这一目标还将决定乳酸如何诱导TAMCs的肌酸生物合成表型。 单位为GBM。 这项建议的第三个目的是检查临床上相关的肌酸转运抑制剂是否会影响 GBM增长。我们将测试这种抑制物在化疗和放射治疗中的作用，以确定如何 肌酸摄取影响基底膜复发。为了从这部作品中建立可翻译的价值，我们将产生 从患者的肿瘤样本和患者来源的异种移植物中筛选肌酸代谢的表达 基因，然后评估对肌酸代谢抑制疗法的敏感性。这一目标的结果将确定是否 阻断TAMC到肿瘤的代谢通讯是GBM治疗的一种可行策略。