biostudies-literatureIshahak MEdward Mallinckrodt, Jr. FoundationAmerican Cancer SocietyNIDDK NIH HHSChristopher Davidson and Knight Family FundNINDS NIH HHSNCI NIH HHSAlvin J. Siteman Cancer Center Siteman Investment ProgramHope Center for Neurological DisordersNIH HHSNational Science FoundationRita Levi-Montalcini Postdoctoral Fellowshipe2410110https://www.ebi.ac.uk/biostudies/studies/S-EPMC11905097biostudies-literatureUnknown12(10)Glioblastoma (GBM) is an aggressive form of brain cancer that is highly resistant to therapy due to significant intra-tumoral heterogeneity. The lack of robust in vitro models to study early tumor progression has hindered the development of effective therapies. Here, this study develops engineered GBM organoids (eGBOs) harboring GBM subtype-specific oncogenic mutations to investigate the underlying transcriptional regulation of tumor progression. Single-cell and spatial transcriptomic analyses revealed that these mutations disrupt normal neurodevelopment gene regulatory networks resulting in changes in cellular composition and spatial organization. Upon xenotransplantation into immunodeficient mice, eGBOs form tumors that recapitulate the transcriptional and spatial landscape of human GBM Advanced science (Weinheim, Baden-Wurttemberg, Germany)Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression.PMC11905097P30 CA091842PF‐21‐149‐01‐CDPR01 NS106612S10 OD026913R25 NS090978T32 DK007120R01 NS128470R25NS090978R01 NS094670PF-21-149-01-CDPAnnamalai DMcCornack CDeSouza PAHan RHCleary RTMillman JRQu XIshahak MWoodiwiss TDahiya SKim AHfalseGenetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression.Glioblastoma (GBM) is an aggressive form of brain cancer that is highly resistant to therapy due to significant intra-tumoral heterogeneity. The lack of robust in vitro models to study early tumor progression has hindered the development of effective therapies. Here, this study develops engineered GBM organoids (eGBOs) harboring GBM subtype-specific oncogenic mutations to investigate the underlying transcriptional regulation of tumor progression. Single-cell and spatial transcriptomic analyses revealed that these mutations disrupt normal neurodevelopment gene regulatory networks resulting in changes in cellular composition and spatial organization. Upon xenotransplantation into immunodeficient mice, eGBOs form tumors that recapitulate the transcriptional and spatial landscape of human GBM 2025-01-01T00:00:00Z2025 Mar2026-06-02T07:19:43.629Z2025-04-05T12:39:08.435ZS-EPMC119050973983654910.1002/advs.202410110