GFAP splice variants fine-tune glioma cell invasion and tumour dynamics by modulating migration persistence

Glioma is the most common form of malignant primary brain tumours in adults. Their highly invasive nature makes the disease incurable to date, emphasizing the importance of better understanding the mechanisms driving glioma invasion. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is characteristic for astrocyte- and neural stem cell-derived gliomas. Glioma malignancy is associated with changes in GFAP alternative splicing, as the canonical isoform GFAP alpha is downregulated in higher-grade tumours, leading to increased dominance of the GFAP delta isoform in the network. In this study, we used intravital imaging and an ex vivo brain slice invasion model. We show that the GFAP delta and GFAP alpha isoforms differentially regulate the tumour dynamics of glioma cells. Depletion of either isoform increases the migratory capacity of glioma cells. Remarkably, GFAP delta-depleted cells migrate randomly through the brain tissue, whereas GFAP alpha-depleted cells show a directionally persistent invasion into the brain parenchyma. This study shows that distinct compositions of the GFAPnetwork lead to specific migratory dynamics and behaviours of gliomas.

Automated summary

Glioma, the most common form of malignant primary brain tumours in adults, is driven by changes in the alternative splicing of glial fibrillary acidic protein (GFAP), which leads to distinct migratory dynamics and behaviours of glioma cells.