Investigating the role of tumor-associated macrophages in glioblastoma multiforme

研究肿瘤相关巨噬细胞在多形性胶质母细胞瘤中的作用

• 批准号: 10205992
• 负责人: Mollie E Chipman
• 金额: $ 4.6万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205992
• 关键词: Adult; Affect; Animal Disease Models; Attention; Biological Models; Bone Marrow; Brain; Brain Neoplasms; CSF1R gene; CSPG4 gene; Cells; Chromium; Complement; Control Groups; Cultured Cells; Data; Development; Diphtheria Toxin; Disadvantaged; Environment; Experimental Designs; Flow Cytometry; Fostering; Foundations; Future; Gene Expression Profiling; Genes; Genetically Engineered Mouse; Genomics; Glioblastoma; Glioma; Goals; Heterogeneity; Histologic; Histology; ITGAM gene; Immune; Immunocompetent; Inflammatory; Institutes; Institution; Journals; Literature; Maintenance; Malignant Neoplasms; Memorial Sloan-Kettering Cancer Center; Mentors; Microglia; Modeling; Molecular; Morphology; Mus; NF1 gene; NF1 mutation; PTPRC gene; Pathway interactions; Physiological; Plant Roots; Play; Population; Prognosis; Publishing; Research Institute; Research Personnel; Resources; Role; Schools; Shapes; Students; Survival Rate; Therapeutic; Time; Tissues; Training; Transplantation; Tumor-associated macrophages; Tumor-infiltrating immune cells; Work; anticancer research; base; cancer therapy; career; early phase clinical trial; experimental study; improved; inhibitor/antagonist; insight; macrophage; monocyte; mouse model; nerve stem cell; novel therapeutics; oligodendrocyte progenitor; preclinical study; single-cell RNA sequencing; stem cells; subventricular zone; success; therapeutic development; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; transplant model; treatment group; tumor; tumor initiation; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis; tumorigenic

Project Summary Glioblastoma Multiforme (GBM) is an aggressive brain tumor with a dismal 5-year survival rate of approximately 5%. Tumor associated macrophages, including tissue resident microglia and bone marrow- derived macrophages, comprise 10-30% of the cells in the tumor, which makes them attractive therapeutic targets. However, preclinical studies performing TAM depletion experiments in mouse models of glioma and GBM have yielded inconsistent results. Additionally, early clinical trials for CSF1R inhibitors, which work by interfering with TAM survival and proliferation, have shown little efficacy despite promising preclinical studies. One shortcoming of all of the preclinical studies that have investigated the role of TAMs in GBM is the use of less ideal, transplantation-based GBM model systems that have only been representative of the proneural GBM subtype. My project aims to improve upon previous studies by performing TAM depletion experiments using highly physiologically relevant, spontaneous genetically engineered mouse models (GEMMs) of GBM derived from two different cells of origin: subventricular zone neural stem cells (NSCs) and oligodendrocyte progenitor cells (OPCs). Additionally, this will be the first time TAM depletion experiments are performed in GEMMs of GBM with an NF1 deficiency, which has been suggested to have a unique role in shaping the GBM microenvironment. TAMs have unique morphologies in the microenvironment of NSC and OPC derived GBMs, suggesting cell of origin may influence TAM function. In addition to depletion studies, we also aim to further characterize the TAM transcriptome in GBM by performing bulk RNAseq on TAMs isolated from spontaneous GEMMs of GBM. As TAM transcriptomic studies performed thus far have suggested the existence of multiple TAM populations within tumors with different functions, we plan to investigate this by performing single-cell RNA-sequencing of TAMs in NSC and OPC derived spontaneous GBMs. Ultimately, the goal of this project is to further decipher the role of TAMs in GBM and in doing so, reveal new therapeutic avenues to treat GBM. Dr. Luis Parada, with his expertise in GBM and animal disease modeling, serves as the ideal sponsor to advise the experimental design and results interpretation throughout the proposed project. He is a supportive and attentive mentor as well, and I am confident that my training will lay the foundation of my success as a future independent investigator. Additionally, Gerstner Sloan Kettering will complement my experimental training with student led journal clubs, seminars, and bi-annual retreats. Also, I am excited to pursue my studies at Sloan Kettering Institute at Memorial Sloan Kettering Cancer Center, a top tier, collaborative cancer research institute that fosters an environment of people that share the goal of improving the prognosis and treatment of cancer. Overall, my sponsor, graduate school, and research institute environment will provide me with the training and resources I need to pursue a career as a cancer biologist at an academic institution.

项目摘要 多形性胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，5年生存率很低， 大约5%。肿瘤相关巨噬细胞，包括组织驻留的小胶质细胞和骨髓- 衍生的巨噬细胞占肿瘤细胞的10-30%，这使得它们具有吸引力的治疗作用 目标的然而，在神经胶质瘤小鼠模型中进行TAM消耗实验的临床前研究和 GBM得出了不一致的结果。此外，CSF 1 R抑制剂的早期临床试验， 干扰TAM存活和增殖的药物，尽管有前景的临床前研究，但几乎没有显示出功效。 所有研究TAM在GBM中作用的临床前研究的一个缺点是使用 不太理想的，基于移植的GBM模型系统，仅代表前神经 GBM亚型。我的项目旨在通过进行TAM消耗实验来改进以前的研究 使用高度生理相关的自发性GBM基因工程小鼠模型（GEMM） 来自两种不同来源的细胞：脑室下区神经干细胞（NSCs）和少突胶质细胞 祖细胞（OPCs）。此外，这将是第一次TAM消耗实验进行， GBM与NF 1缺陷的GEMM，已被认为在形成GBM中具有独特的作用 微环境TAM在NSC和OPC衍生的GBM的微环境中具有独特的形态， 提示来源细胞可能影响TAM功能。除了消耗研究，我们还旨在进一步 通过对从GBM中自发分离的TAM进行批量RNAseq， GBM的GEMM。由于TAM转录组学研究迄今为止已经表明存在多个 TAM群体在肿瘤中具有不同的功能，我们计划通过进行单细胞 NSC和OPC衍生的自发GBM中TAM的RNA测序。最终，这个项目的目标是 进一步解释TAM在GBM中的作用，并在此过程中揭示了治疗GBM的新的治疗途径。 Luis Parada博士凭借其在GBM和动物疾病建模方面的专业知识， 就整个拟议项目的实验设计和结果解释提供建议。他是一个 支持和周到的导师，以及，我相信我的培训将奠定我的基础， 作为未来的独立调查员。此外，郭士纳斯隆凯特琳将补充我的 通过学生领导的期刊俱乐部、研讨会和两年一度的务虚会进行实验培训。我也很高兴 我在纪念斯隆凯特琳癌症中心的斯隆凯特琳研究所继续学习，这是一个顶级的研究所， 合作癌症研究所，促进人们的环境，共同改善的目标， 癌症的预后和治疗。总的来说，我的赞助商，研究生院和研究所 环境将为我提供所需的培训和资源，以追求作为癌症生物学家的职业生涯， 学术机构

项目成果

Tumor progression is independent of tumor-associated macrophages in cell lineage-based mouse models of glioblastoma.

• DOI: 10.1073/pnas.2222084120
• 发表时间: 2023-04-18
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Chipman ME;Wang Z;Sun D;Pedraza AM;Bale TA;Parada LF
• 通讯作者: Parada LF