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.

项目概要/摘要 胶质母细胞瘤（GBM）是成人中最常见的脑肿瘤恶性肿瘤，其特点是 称为假栅栏坏死的壁龛。这些缺氧区域是该疾病的一个决定性特征， 促进化学抗性、放射抗性，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该疾病至关重要。 对人类 GBM 患者的多组学分析表明，肌酸转运蛋白 Slc6a8 是特异性的 由缺氧和坏死区域的肿瘤细胞表达。这些区域周围是肿瘤相关的 骨髓细胞（TAMC），是 GBM 中最丰富的浸润免疫细胞。令人惊讶的是，TAMC 围绕缺氧假栅栏区域的细胞表达产生肌酸所需的酶。 因此，我们假设 TAMC 衍生的肌酸促进了假栅栏的产生 GBM 中的坏死生态位，并且这种代谢串扰促进 GBM 健康和治疗抵抗。 先前的工作已经确定缺氧的假栅栏生态位含有神经胶质瘤干细胞（GSC）， 这是由这些区域内的缺氧应激产生的。此外，Slc6a8 直接受 缺氧，表明肌酸摄取对 GSC 表型有影响。因此，本提案的首要目标是 研究肌酸转运如何影响人类和小鼠 GBM 模型中的 GSC 表型。在这个 目标，我们还将利用 GBM 的诱导模型来概括人类的遗传和病理特征 GBM 确定 Slc6a8 是否对于肿瘤中缺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 的小鼠和人类中分离出的 TAMC 是有效的 肌酸生产商。此外，我们发现这种代谢表型是肿瘤特有的 微环境（TME）并由细胞外乳酸诱导。因此，本提案的第二个目标是 研究 TAMC 消除肌酸生物合成如何控制小鼠肿瘤的生长和进展 GBM 模型。这一目标还将确定乳酸如何诱导 TAMC 的肌酸生物合成表型 在GBM中。 该提案的第三个目的是检查临床相关的肌酸转运抑制剂是否会影响 GBM 生长。我们将测试这种抑制剂在化疗和放疗背景下如何发挥作用，以确定如何 肌酸摄取影响 GBM 复发。为了从这项工作中建立可翻译的价值，我们将生成 肿瘤样本和患者来源的异种移植物，筛选它们的肌酸代谢表达 基因，然后评估对肌酸代谢抑制治疗的敏感性。这一目标的结果将确定是否 阻断 TAMC 与肿瘤代谢通讯是 GBM 治疗的可行策略。