A Multi-Omic Phenobank Reveals Axes of Glioblastoma Growth, Invasion, and Therapeutic Vulnerability.
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Krona C, Kundu S, Rosen E, Kruse F, Skeppås M, Babačić H, Larsson I, Elfineh L, Lü MJS, Conde ME, Elgendy R, Dave Z, Doroszko M, Rut-Halldorsdottir K, Cao X, Ramachandra R, Olausson KH, Nilsson M, Weischenfeldt J, Wikström J, Pernemalm M, Sundström A, Uppman I, Mangukiya HB, Nelander S
Neuro-oncology - (-) - [2026-10-12; online 2026-10-12]
Glioblastoma (GBM) invasion is clinically decisive but difficult to model systematically. Existing patient-derived xenograft (PDX) resources rarely couple reproducible in vivo invasion phenotypes with matched multi-omic profiles at scale, limiting mechanistic insight and phenotype-informed therapeutic hypotheses. We established the HGCC Phenobank, comprising 65 patient-derived GBM stem-like cultures with matched multi-omic profiling and orthotopic engraftment in 449 mice. Blinded histopathology quantified ten invasion traits per case. These phenotypes were integrated with RNA sequencing, DNA methylation, and mass-spectrometry-based proteomics. Multi-Omic Factor Analysis (MOFA) identified latent molecular programs. Phenotype-specific RNA signatures were matched to LINCS drug-perturbation profiles and validated in 3D gliomasphere and ex vivo brain-slice assays. Two dominant, reproducible invasion modes emerged across models: diffuse parenchymal infiltration and perivascular/condensed growth. Proneural cultures formed more aggressive tumors in immunodeficient mice, and mouse survival showed a modest correlation with patient survival in matched cases (Pearson r=0.1832, p=0.045). MOFA identified 15 latent factors; Factor 1, marked by ASCL1/OLIG1/OLIG2 programs across multiple molecular layers, was associated with increased tumor formation and diffuse invasion in mice. Higher Factor 1 scores were associated with significantly longer postoperative survival in both the matched patient cohort (p = 0.00018) and TCGA (p = 0.017), although Factor 1 was not associated with survival of the xenografted mice. Drug-signature matching separated mechanisms targeting diffuse versus perivascular invasion. Experimental validation confirmed phenotype-selective sensitivities, and inhibitors PIK-75 and buparlisib suppressed invasion dynamics across representative models in 3D and brain-slice assays. The HGCC Phenobank provides the first openly available PDX resource that systematically links GBM invasion phenotypes to multi-omic programs and therapeutic predictions. This framework enables reproducible model selection, mechanistic dissection of invasion modes, and phenotype-guided therapeutic discovery.
NGI Uppsala (SNP&SEQ Technology Platform) [Service]
National Genomics Infrastructure [Service]
PubMed 42865025
DOI 10.1093/neuonc/noag255
Crossref 10.1093/neuonc/noag255
pii: 8911843