ArticleFrontiers in oncology2026
Tumor-neuronal hybrid programs reveal a spatially adaptive malignant state in glioblastoma.
Article in Frontiers in oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Objective: Glioblastoma (GBM) exhibits marked cellular plasticity, including partial acquisition of neuron-associated transcriptional features. We tested whether public GBM spatial and single-nucleus datasets reveal a tumor-neuronal program with spatial organization and distinction from canonical proneural-like identity. Methods: We re-analyzed public multi-region GBM spatial transcriptomic data from Greenwald et al. and used healthy cortex data from Ravi et al. as a non-malignant reference. Tumor-neuronal (TN) classifications were defined by concurrent enrichment of malignancy-associated and neuronal-associated gene programs using permutation-derived empirical thresholds. Classification stability was assessed by bootstrap resampling, repeated threshold estimation, and Jaccard overlap. Greenwald-derived CNA/malignancy scores were used to evaluate tumor-associated signal in TN-classified spatial units. External validation was performed in an independent Wang malignant GBM-cell/single-nucleus dataset, including held-out TN-specific scoring after excluding genes used in the original scoring programs. Exploratory bulk-cohort analysis was performed in TCGA GBM. Results: TN-classified spatial units were detected across tumor regions at higher frequency than healthy cortex and showed regional organization within the spatial discovery specimen. They expressed synaptic and vesicle-associated genes, including SYT1 and STMN2, while retaining malignant/glial-associated features such as GFAP, VIM, and CLU. Mature neuronal subtype markers were less enriched, supporting partial neuronal mimicry rather than lineage conversion. TN-associated genes formed a connected protein-interaction network centered on synaptic, neurite-associated, and cytoskeletal proteins. CNA/malignancy-score analysis showed tumor-associated signal in TN-classified spatial units. In the Wang malignant GBM-cell validation dataset, TN-classified cells/nuclei retained held-out TN-specific enrichment relative to non-TN and proneural-high non-TN malignant cells/nuclei. Conclusion: Public spatial and single-nucleus GBM datasets identify a tumor-associated neuronal mimicry program that is spatially organized in a GBM discovery specimen and detectable in an independent malignant-cell validation dataset. This program is proneural-adjacent but not reducible to canonical proneural identity.
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