Abstract
Glioblastoma multiforme is one of the most lethal cancers worldwide. Despite intensive multimodal therapy, including fractionated irradiation, recurrence is almost universal due to persistence of glioma stem-like cells (GSC) with strong intrinsic or acquired radioresistance. More targeted and efficient high-LET radiation regimens are under investigation, but limited insight into the complex DNA damage and repair hamper routine implementation. A better understanding of the behaviour of GSC post-irradiation, demands an accurate quantification of repair pathways and their interactions, ideally at the level of the individual lesion. That is why we will develop a technique that combines state-of-the-art expansion microscopy with cyclic staining to quantify the recruitment and dissolution of repair factors at DNA damage sites with close-to-nano-scale resolution. After benchmarking the established method with known repair modulators, we intend to apply this strategy to a panel of patient derived GSC with varying characteristics exposed to low- and high-LET radiation. We will directly relate the individual response to radiation to the cellular phenotype, tumour qualification and transcriptional data. In parallel, we aim to unveil additional repair markers in astrocytes by performing proteomics experiments. This way, we intend to improve our mechanistic understanding into the molecular rewiring of gliomas causing treatment resistance and recurrence.
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