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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘