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<https://archiv.ub.uni-heidelberg.de/volltextserver/id/eprint/33039> <http://purl.org/ontology/bibo/abstract> "Glioblastoma is the most common central nervous system malignancy in adults with a very poor\r\noutcome due to its invasiveness, intratumoral heterogeneity, poorly differentiated features, and\r\nimmunosuppressive microenvironment. Previous work suggested that Branched-chain amino\r\nacid transaminase 1 (BCAT1) is often highly expressed in glioblastoma and multiple modes of\r\naction for its oncogenic potential have been proposed. In this thesis, I focus on investigating a\r\nnovel role of BCAT1 in maintaining mitotic fidelity, and how it impacts the cellular plasticity of\r\nglioblastoma cells and the tumor immune microenvironment.\r\nWe have found that BCAT1 localizes to the key mitotic structures during cell division as well as in\r\nthe nucleus during interphase. Using co-immunoprecipitation mass spectrometry, I showed that\r\nBCAT1 associates with many components of the mitotic spindle and the kinetochore during\r\nmitosis. Through proteomic and phosphoproteomic analysis I showed that the central kinases of\r\nthe spindle assembly checkpoint, TTK and AURKB, showed significantly decreased activity during\r\nmitosis upon BCAT1-KO.\r\nBy analyzing the expression patterns of human and mouse glioblastoma cells and tumor samples\r\nof the TCGA-GBM cohort, I found that BCAT1 expression is strongly correlated with the cellular\r\nstate of glioblastoma, with high expression being indicative of a mesenchymal phenotype and low\r\nor no expression with a neuronal cellular state. I further confirmed these observations through a\r\nseries of differentiation experiments of murine glioblastoma stem cells where the Bcat1-KO\r\nshowed a much higher tendency towards differentiation and lacked the plasticity of the control\r\ncells. Consistently, in vivo findings corroborated these results with a complete lack of tumor\r\noutgrowth of the Bcat1-KO cells in immunocompetent mice, and a significant growth delay in\r\nimmunodeficient mice.\r\nLastly, I explored the impact of tumor BCAT1 expression on the immune microenvironment. I\r\nfound that low BCAT1 expression was associated with a higher immune infiltration of both myeloid\r\nand T-cells in human tumor samples. These findings were additionally confirmed in in vivo\r\nexperiments in immunocompetent mice. Furthermore, Bcat1-KO tumors did develop in the\r\nimmunodeficient NSG and Rag2KO mouse models, highlighting the importance of the immune\r\ncompartment in completely abrogating their growth.\r\nIn conclusion, the data presented here confirm the novel role of BCAT1 in maintaining mitotic\r\nfidelity of glioblastoma cells. Furthermore, it shows that BCAT1 expression is necessary for\r\nmaintaining the plasticity of glioblastoma cells and an immunosuppressive tumor\r\nmicroenvironment."^^<http://www.w3.org/2001/XMLSchema#string> .
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