A grasp on GFAP in Glioma: From tumour cell invasion to nuclear fragmentation

Abstract

This thesis aimed to better understand the function and relevance of the GFAP protein in glioma biology. We have shown that GFAP plays a dual role in glioma cell invasion. First of all, we show that GFAP isoforms distinctively facilitate cell invasion into the brain parenchyma. In GFAPδ/α-high cells, increased dominance of GFAPδ leads to molecular alterations that equip cells to better infiltrate confined spaces using adhesion based migration modes. This includes 1) increased deposit of ECM proteins (laminin), 2) alterations in the expression of genes involved in ECM remodelling (MMPs and A2M) and 3) alterations in the expression of genes that facilitate binding to the native and self-produced matrix (ITGA6, ITGA7, ITGB1). These molecular alterations lead to slow, but directional cell invasion into the brain parenchyma resulting in a diffuse growth pattern. A GFAPδ/α-low ratio on the other hand has the opposite effect on migration persistence. Cells with low GFAPδ/α ratios are highly motile, but migrate in a random fashion. In addition to facilitating specific forms of migration, GFAP protects the cell from migration induced nuclear and cellular damage in an isoform independent manner. On top of these functional roles of GFAP, we show that GFAP in serum is specifically elevated in grade IV patients, opening up avenues of research for GFAP as a serum biomarker. Altogether, we propose that GFAP and other IF proteins play a major role in glioma cell-environment reciprocity, where environmental factors affect the composition and organisation of the IF network, and the IF network affects how a cell interacts with its environment. All in all, in our aim of getting a better grasp on GFAP in glioma, we discovered that GFAP is not only a marker to identify tumours of glial origin, but that it also plays a broad functional role in glioma behaviour, from regulating cell invasion to protecting the cell against migration inducted nuclear fragmentation.