Intermediate filaments promote glioblastoma cell invasion by controlling nuclear deformations and mechanosensitive expression of MMP14

Abstract

Glioblastoma (GBM), the most aggressive primary brain tumor, is marked by high invasiveness that enables resistance to current therapies. Single-cell RNA sequencing analysis reveals that elevated expression of glial intermediate filament (IF) genes correlates with pro-invasive markers in GBM samples. Notably, vimentin expression correlates with a lower survival rate. Functional assays demonstrate that cytoplasmic IFs, despite reducing GBM cell deformability, enhance 3D invasion both in vitro and in vivo. Mechanistically, IFs support leader cell invasion through mechanosensitive matrix degradation by buffering nuclear deformations under compressive stress. Moreover, IFs correlate with high matrix metalloproteinase (MMP)14 levels in patients and activate MMP14 production in vitro. These findings reveal the crucial role of IFs in promoting GBM cell invasion and suggest that IF expression can serve as a molecular marker of invading GBM cells.