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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270083 | GEO | 2025/06/15

REPOSITORIES: GEO

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Project description:Glioblastoma (GBM) is the most common primary malignant brain tumor, with patients exhibiting poor survival (median survival time: 15 months). Difficulties in treating GBM include not only the inability to resect the diffusively-invading tumor cells but also therapeutic resistance. The perivascular niche within the GBM tumor microenvironment contributes significantly to tumor cell invasion, cancer stem cell maintenance, and has been shown to protect tumor cells from radiation and chemotherapy. In this study, we describe the development of an in vitro artificial perivascular niche (PVN), culturing endothelial and stromal cells along with GBM cells within a methacrylamide-functionalized gelatin hydrogel, in order to examine how the presence of the PVN alters global genomic expression profiles. Using RNA-seq, we demonstrate that the inclusion of perivascular niche cells with GBM cells upregulates genes related to angiogenesis and remodeling, while downregulated genes are related to cell cycle and DNA damage repair. Signaling pathways and genes commonly implicated in GBM malignancy, such as MGMT, EGFR, PI3K-Akt signaling, and Ras/MAPK signaling are also upregulated in the presence of perivascular niche cells. We describe the kinetics of gene expression within the PVN hydrogels over a course of 14 days, observing the patterns associated with previously-observed GBM-mediated endothelial network co-option and regression that are altered in the presence of covalently-bound hyaluronic acid. We finally examine the effect of PVN culture on GBM cell responsiveness to temozolomide, a frontline chemotherapy used clinically against GBM. Notably, the presence of a PVN leads to significantly increased TMZ resistance compared to hydrogels containing only GBM cells. Overall, these results demonstrate that inclusion of cellular and matrix-associated elements of the PVN within in vitro models of GBM provide critical signals to regulate the phenotype and therapeutic responsiveness of GBM cells.

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

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