Investigating the role of tumor-associated macrophages in glioblastoma multiforme

项目摘要 多形性胶质母细胞瘤(GBM)是一种侵袭性的脑瘤，5年生存率令人沮丧。 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%，这使它们具有治疗吸引力 目标。然而，在小鼠胶质瘤模型和脑胶质瘤模型上进行耗竭实验的临床前研究 GBM产生了不一致的结果。此外，CSF1R抑制剂的早期临床试验通过 干扰的存活和增殖，尽管临床前研究前景看好，但效果甚微。 所有研究TAMs在GBM中的作用的临床前研究的一个缺点是使用了 不太理想的、基于移植的GBM模型系统，仅代表原发组织 GBM亚型。我的项目旨在通过进行耗竭实验来改进以前的研究 使用高度生理相关的自发基因工程小鼠模型(GEMM)的GBM 来源于两种不同来源的细胞：脑室下区神经干细胞和少突胶质细胞 祖细胞(OPC)。此外，这将是首次在中国进行耗竭实验。 具有NF1缺陷的GBM的GEMM，这被认为在形成GBM方面具有独特的作用 微环境。TAM在NSC和OPC衍生的GBM的微环境中具有独特的形态， 提示细胞来源可能影响的功能。除了枯竭研究外，我们还致力于进一步 对自发分离的TAM进行Bulk RNAseq分析转录组的特征 GBM的GEMM。正如到目前为止进行的转录研究表明，存在多个 群体内的肿瘤具有不同的功能，我们计划通过进行单细胞实验来研究这一点 NSC和OPC来源的自发性GBM中TAMs的RNA测序。最终，这个项目的目标是 为了进一步破译TAMs在GBM中的作用，并以此揭示治疗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，是理想的赞助商 在整个拟议项目中，为实验设计和结果解释提供建议。他是一个 我相信我的训练将为我的未来奠定基础。 成功地成为一名未来的独立调查员。此外，格斯特纳·斯隆·凯特林将补充我的 与学生主导的期刊俱乐部、研讨会和每两年举行一次的静修活动一起进行实验培训。另外，我也很兴奋能 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，这是一流的， 协作性癌症研究机构，培养人们共享改善目标的环境 癌症的预后和治疗。总体而言，我的赞助商、研究生院和研究所 环境将为我提供从事癌症生物学家职业所需的培训和资源 一个学术机构。

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.