TY - JOUR
T1 - GFAP splice variants fine-tune glioma cell invasion and tumour dynamics by modulating migration persistence
AU - Uceda-Castro, Rebeca
AU - van Asperen, Jessy V.
AU - Vennin, Claire
AU - Sluijs, Jacqueline A.
AU - van Bodegraven, Emma J.
AU - Margarido, Andreia S.
AU - Robe, Pierre A.J.
AU - van Rheenen, Jacco
AU - Hol, Elly M.
N1 - Funding Information:
The results shown here are partly based on data generated by The Cancer Genome Atlas Research Network (https://www.cancer.gov/tcga). The authors thank all members of the Hol and van Rheenen labs for thoughtful discussion. This study was funded by the Dutch Cancer Society [KWF 101123, R.U.C, J.v.A, J.v.R, E.H.], a HFSP fellowship (C.V.), the Portuguese Foundation for Science and Technology (FCT, GABBA program-PD/ BD/105748/2014, A.S.M.), the T and P Bohnenn Foundation (P.R) and the Josef Steiner Foundation (J.v.R).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/1/10
Y1 - 2022/1/10
N2 - 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 GFAPα is downregulated in higher-grade tumours, leading to increased dominance of the GFAPδ isoform in the network. In this study, we used intravital imaging and an ex vivo brain slice invasion model. We show that the GFAPδ and GFAPα isoforms differentially regulate the tumour dynamics of glioma cells. Depletion of either isoform increases the migratory capacity of glioma cells. Remarkably, GFAPδ-depleted cells migrate randomly through the brain tissue, whereas GFAPα-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.
AB - 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 GFAPα is downregulated in higher-grade tumours, leading to increased dominance of the GFAPδ isoform in the network. In this study, we used intravital imaging and an ex vivo brain slice invasion model. We show that the GFAPδ and GFAPα isoforms differentially regulate the tumour dynamics of glioma cells. Depletion of either isoform increases the migratory capacity of glioma cells. Remarkably, GFAPδ-depleted cells migrate randomly through the brain tissue, whereas GFAPα-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.
UR - http://www.scopus.com/inward/record.url?scp=85122722715&partnerID=8YFLogxK
U2 - 10.1038/s41598-021-04127-5
DO - 10.1038/s41598-021-04127-5
M3 - Article
C2 - 35013418
AN - SCOPUS:85122722715
SN - 2045-2322
VL - 12
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 424
ER -