GFAP alternative splicing regulates glioma cell–ECM interaction in a DUSP4‐dependent manner

Abstract

Gliomas are the most common primary brain tumors. Their highly invasive character and the heterogeneity of active oncogenic pathways within single tumors complicate the development of curative therapies and cause poor patient prognosis. Glioma cells express the intermediate filament protein glial fibrillary acidic protein (GFAP), and the level of its alternative splice variant GFAP‐δ, relative to its canonical splice variant GFAP‐α, is higher in grade IV compared with lower‐grade and lower malignant glioma. In this study we show that a high GFAP‐δ/α ratio induces the expression of the dual‐specificity phosphatase 4 (DUSP4) in focal adhesions. By focusing on pathways up‐ and downstream of DUSP4 that are involved in the cell‐extracellular matrix interaction, we show that a high GFAP‐δ/α ratio equips glioma cells to better invade the brain. This study supports the hypothesis that glioma cells with a high GFAP‐δ/α ratio are highly invasive and more malignant cells, thus making GFAP alternative splicing a potential therapeutic target.—Van Bodegraven, E. J., van Asperen, J. V., Sluijs, J. A., van Deursen, C. B. J., van Strien, M. E., Stassen, O. M. J. A., Robe, P. A. J., Hol, E. M. GFAP alternative splicing regulates glioma cell–ECM interaction in a DUSP4‐dependent manner. FASEB J. 33, 12941–12959 (2019). http://www.fasebj.org

GFAP at 50

“…The functions of the minor isoforms, as for GFAPα, are poorly understood. Speculation has focused on potential roles for GFAPδ in stem cells ( Roelofs et al., 2005 ; van den Berge et al., 2010 ) and gliomas ( Moeton et al., 2016 ; Stassen et al., 2017 ; van Bodegraven et al., 2019b ). No animal models have yet been made to selectively express or delete a specific isoform.…”

“…One of these is vanishing white matter disease, which like Alexander disease is a primary disorder of astrocytes ( Bugiani et al., 2011 ; Huyghe et al., 2012 ; Dooves et al., 2016 ; Zhou et al., 2019 ). A second is a subset of astrocytoma patients with poor outcome ( van Bodegraven et al., 2019b ). The authors suggest that the poor prognosis is due to the elevated GFAPδ/GFAPα ratio causing upregulation of the phosphatase dual-specificity phosphatase-4 (DUSP4), with speculation involving mitogen-activated protein kinase signaling pathways and interactions with the extracellular matrix.…”

New GFAP splice isoform (GFAPμ) differentially expressed in glioma translates into 21 kDa N-terminal GFAP protein

“…We have observed that in high malignant glioma the relative level of the alternative splice variant GFAPδ to the canonical variant GFAPα is increased compared to lower malignant glioma (Stassen et al, 2017) and in vitro studies suggest that changes in the relative level of GFAPδ to GFAPα have functional implications for glioma (Moeton et al, 2014;Stassen et al, 2017;van Bodegraven et al, 2019b). These studies emphasize the importance of discriminating between GFAP splice variants when studying the role of GFAP in glioma malignancy and using GFAP as a diagnostic marker (van Bodegraven et al, 2019a).…”

“…Induced overexpression of the self-assembly incompetent GFAPδ isoform in glioma cells disrupts the IF network of glioma cells as well (Moeton et al, 2016). However, increased endogenous GFAPδ protein leaves the IF network intact and impacts glioma cell malignant behavior (van Bodegraven et al, 2019b). In these cells, higher levels of GFAPδ are observed within the IF network.…”

“…Glioma consist of a heterogeneous population of GFAP positive cells (van Bodegraven et al, 2019a). We previously described that the increased relative expression of GFAPδ to GFAPα might distinguish a GFAP positive subpopulation of high malignant glioma cells with invasive characteristics (Stassen et al, 2017;van Bodegraven et al, 2019b;a). As GFAPµ expression was decreased in high malignant glioma and absent in GFAP expressing ihNSCs and adult neural stem cells, we hypothesize (WHO 2007) and in different glioma subtypes (WHO2016).…”