Research Isa Decuypere

Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor. Central to the disease is the presence of glioma stem-like cells (GSCs), which have the capacity to self-renew and change phenotype. However, the factors governing their cell state transitions and invasion patterns remain unclear. I hypothesize that the dense, stiff tumor microenvironment and mechanical forces during migration render GSCs vulnerable to nuclear envelope (NE) stress, a pathogenic process that compromises cell homeostasis and promotes DNA damage. With this project, I will investigate whether NE stress is a driver of cell state plasticity and GBM disease progression. To this end, I will quantify the cell state-dependent sensitivity to well-controlled mechanical stimuli in a panel of patient-derived GSCs. I will validate my findings and relate them to the invasive potential using a cerebral organoid infiltration model. Next, I will exploit spatial-selective proteomics and transcriptomics to identify GBM-specific responses to induced NE stress. I will then use pharmacogenetic modulations to unravel the synthetic lethal potential of putative hits and evaluate their in vivo relevance in patient-derived biopsy sections. By approaching the pathology from a biophysical perspective, I will generate novel insights into the penetrance and cell state dependence of NE stress, and in doing so, I intend to expose selective, targetable vulnerabilities of GBM.

Researcher(s)

• Promoter: De Vos Winnok
• Fellow: Decuypere Isa

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: De Vos Winnok
• Fellow: Decuypere Isa

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project