Abstract
Glioblastoma multiforme (GBM) is one of the most lethal tumors, due to its high heterogeneity, extensive infiltration, and cell state plasticity. Recurrence is almost universal, and there is no cure, thus urging for novel research angles. The dense and stiff tumor microenvironment exposes GBM cells to significant mechanical force. We hypothesize this renders them vulnerable to nuclear envelope (NE) stress, a process that promotes DNA damage and might contribute to tumor aggressiveness. Hence, with this project, we will investigate the contribution of NE stress to the development of GBM. To do so, we will systematically characterize the NE composition and dynamics in a panel of patient derived stem-like GBM cells (GSC) of varying aggressiveness. Then, we will evaluate how these cells respond to changes in substrate stiffness or confinement and we will identify proteins that drive their response using proximity proteomics. Finally, we will dissect the effects of chronic NE stress on cancer progression, by studying genome instability and invasiveness of GSC in cerebral organoids as relevant model systems that mimic part of the in vivo context. Together, this work will expose the impact of derailed nuclear mechanics on GBM development and may unveil new leads for its therapeutic targeting.
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