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Abstract

Glioblastoma (GBM) is the most aggressive tumor of the central nervous system. Median survival time is 15 months from diagnosis. Standard of care for GBM patients includes surgery, radiation and chemotherapy. All known therapies for GBM patients do not lead to prolonged survival. Some targeted therapies can lead to a prolonged progression free survival. Overall survival of patients however is not increased by any available therapy option. MEOX2 is a homeobox-transcription factor. It is highly upregulated during embryogenesis and responsible for the development of muscles, angiogenesis and limb development. MEOX2 can regulate the epithelial-mesenchymal transition of cells via cyclin dependent kinase signaling. MEOX2 is not expressed in the adult brain tissue however is significantly upregulated in GBM and correlates with tumor grade. High MEOX2 expression in gliomas is generally correlated with a worse clinical prognosis for patients, underlining the potential role of MEOX2 in tumorigenesis. As current therapy options can not provide a cure for GBM, it is crucial to understand the role of MEOX2 and reveal candidates connected to the malignant transformation of gliomas for further investigations. In a lower grade progression free state, glioma could be treated like a chronic disease. Therefore, I identified MEOX2 regulatory effect on cancer associated pathways and unraveled the target genes of MEOX2 in two GBM patient-derived tumorsphere lines. I also identified an ERK phosphorylation site in MEOX2 in the GBM tumorsphere line (S155) and elucidated the nuclear MEOX2 protein distribution depending on its phosphorylation status. I was also able to identify MEOX2 as an oncogene in vivo, using a xenograft mouse model where I observed increased proliferation upon MEOX2 overexpression in a GBM tumorsphere line that exhibits slower growth kinetics. Lastly, I observed MEOX2 knockdown in one of two GBM tumorsphere lines reduced sensitivity to EGF activated ERK phosphorylation that was reversed by a MEK inhibitor. All results indicate a role of MEOX2 as an oncogene in gliomas, and MEOX2 may serve as a future prognostic marker in gliomas. It is favourable to identify GBM in an early state which is currently not possible due to diagnosis based on MRI scans, this way GBM has a lower amount of lesions and accumulated mutations, which are gained in tumor development.