The Department of Biomedicine

BBB seminar: Frank A. E. Kruyt

Stressing out glioblastoma cells: Endoplasmic reticulum stress and the unfolded protein response as targets for therapy

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Frank A. E. Kruyt
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, The Netherlands

Glioblastoma (GBM) is the most aggressive form of brain cancer. Currently, available treatments have only limited efficacy resulting in a poor prognosis of patients with GBM. Highly invasive growth, cellular heterogeneity and resistance to (chemo)therapy are major characteristics of GBM that hamper successful treatment of patients. The identified cancer stem cells in GBM (GSCs) are believed to be main players in these detrimental features.

The endoplasmic reticulum (ER) is an organelle responsible for synthesis and correct folding of proteins and their vesicular intra- and extracellular transport. The quality of these processes is controlled by the so-called ER-stress/unfolded protein response (UPR). This is an adaptive signaling pathway allowing cells to resolve disruption of protein homeostasis, or activate cell death when damage is overwhelming. Clearly, the UPR is essential for cellular homeostasis under physiological and pathological conditions. Due to a high demand of cancer cells for protein synthesis and secretion, and their exposure to harsh microenvironmental conditions, cancer cells (including GBM) often display a chronic activated UPR. Hence, aggravation of ER stress or disrupting UPR signaling is a promising therapeutic approach.

In this presentation recent results from my lab are shown on the exploration of the therapeutic potential of ER stress induction in GBM. Neuropshere/GSC cell culture models were used to examine sensitivity to ER stress in proneural and mesenchymal GSCs and serum-differentiated counterparts. Overall, this revealed strong sensitivity of GBM cells to ER stress, although interestingly the differentiation status was associated with substantial differences in sensitivity. To understand better the underlying mechanisms the involvement of the three different UPR branches, IRE1, PERK and ATF6, was examined. This indicated an important role for PERK. Using RNAseq and co-immunoprecipitation experiments further mechanistic insights were obtained. These findings and the relevance of the ER-UPR as a target for therapy in GBM is further presented and discussed.

In conclusion, the ER-UPR appears to be a promising target for therapy in GBM.

Chairperson: Hrvoje Miletic, Department of Biomedicine