The invasion phenotypes of glioblastoma depend on plastic and reprogrammable cell states

Glioblastoma (GBM), the most common primary brain cancer in adults, is characterized by rapid local invasion along diverse routes, such as infiltration of white matter tracts and penetration of perivascular spaces. We investigate the hypothesis that GBM invasion routes correlate with the transcriptional states of individual cells and identify regulators of route-specific invasion. Utilizing patient-derived GBM xenograft models, we integrate single-cell transcriptomics and spatial proteomics, revealing that mesenchymal and oligodendrocyte progenitor-like GBM cells migrate perivascularly, while neural progenitor and astrocyte-like GBM cells invade diffusely. Computational reconstruction identifies ANXA1 as a perivascular invasion driver and lineage-restricted transcription factors RFX4 and HOPX as drivers of diffuse invasion, predictive of patient survival. Genetic ablation of these genes alters invasion phenotypes and extends survival in xenografted mice, clarifying the role of cell states in GBM invasion, and highlighting potential therapeutic targets for selective invasion route targeting in GBM patients.