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.
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor in adults with a dismal median survival of 14.6 months. This project aims to further understand the role of tumor-associated macrophages in the GBM microenvironment by depleting these cells in GBM mouse models to determine if the tumor is inhibited, promoted, or unaffected. Ultimately, the results from this study will provide a better understanding of the role of tumor-associated macrophages in GBM and provide insight on how to exploit these cells to create better therapies for GBM.
