Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression
Abstract 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 eng...
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| Format: | Article |
| Language: | English |
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202410110 |
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| author | Matthew Ishahak Rowland H. Han Devi Annamalai Timothy Woodiwiss Colin McCornack Ryan T. Cleary Patrick A. DeSouza Xuan Qu Sonika Dahiya Albert H. Kim Jeffrey R. Millman |
| author_facet | Matthew Ishahak Rowland H. Han Devi Annamalai Timothy Woodiwiss Colin McCornack Ryan T. Cleary Patrick A. DeSouza Xuan Qu Sonika Dahiya Albert H. Kim Jeffrey R. Millman |
| author_sort | Matthew Ishahak |
| collection | DOAJ |
| description | Abstract 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 samples. Integrative single‐cell trajectory analysis of both eGBO‐derived tumor cells and patient GBM samples reveal the dynamic gene expression changes in developmental cell states underlying tumor progression. This analysis of eGBOs provides an important validation of engineered cancer organoid models and demonstrates their utility as a model of GBM tumorigenesis for future preclinical development of therapeutics. |
| format | Article |
| id | doaj-art-4de2491f856d4fb98e7324f098c8fd0b |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-4de2491f856d4fb98e7324f098c8fd0b2025-08-20T03:46:46ZengWileyAdvanced Science2198-38442025-03-011210n/an/a10.1002/advs.202410110Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma ProgressionMatthew Ishahak0Rowland H. Han1Devi Annamalai2Timothy Woodiwiss3Colin McCornack4Ryan T. Cleary5Patrick A. DeSouza6Xuan Qu7Sonika Dahiya8Albert H. Kim9Jeffrey R. Millman10Division of Endocrinology Metabolism and Lipid Research Washington University School of Medicine 660 South Euclid Avenue, Campus Box 8127 St. Louis MO 63110 USADepartment of Genetics Washington University School of Medicine 4515 McKinley Ave. St. Louis MO 63110 USADepartment of Genetics Washington University School of Medicine 4515 McKinley Ave. St. Louis MO 63110 USADepartment of Neurological Surgery University of Iowa Healthcare 1800 John Pappajohn Pavilion Iowa City IA 52242 USADepartment of Genetics Washington University School of Medicine 4515 McKinley Ave. St. Louis MO 63110 USADepartment of Genetics Washington University School of Medicine 4515 McKinley Ave. St. Louis MO 63110 USADepartment of Genetics Washington University School of Medicine 4515 McKinley Ave. St. Louis MO 63110 USADepartment of Genetics Washington University School of Medicine 4515 McKinley Ave. St. Louis MO 63110 USADivision of Neuropathology Washington University School of Medicine 660 South Euclid Avenue, Campus Box 8118 St. Louis MO 63110 USADepartment of Genetics Washington University School of Medicine 4515 McKinley Ave. St. Louis MO 63110 USADivision of Endocrinology Metabolism and Lipid Research Washington University School of Medicine 660 South Euclid Avenue, Campus Box 8127 St. Louis MO 63110 USAAbstract 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 samples. Integrative single‐cell trajectory analysis of both eGBO‐derived tumor cells and patient GBM samples reveal the dynamic gene expression changes in developmental cell states underlying tumor progression. This analysis of eGBOs provides an important validation of engineered cancer organoid models and demonstrates their utility as a model of GBM tumorigenesis for future preclinical development of therapeutics.https://doi.org/10.1002/advs.202410110brain organoidsgenetic engineeringglioblastomasingle‐cell RNA sequencingspatial sequencing |
| spellingShingle | Matthew Ishahak Rowland H. Han Devi Annamalai Timothy Woodiwiss Colin McCornack Ryan T. Cleary Patrick A. DeSouza Xuan Qu Sonika Dahiya Albert H. Kim Jeffrey R. Millman Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression Advanced Science brain organoids genetic engineering glioblastoma single‐cell RNA sequencing spatial sequencing |
| title | Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression |
| title_full | Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression |
| title_fullStr | Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression |
| title_full_unstemmed | Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression |
| title_short | Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression |
| title_sort | genetically engineered brain organoids recapitulate spatial and developmental states of glioblastoma progression |
| topic | brain organoids genetic engineering glioblastoma single‐cell RNA sequencing spatial sequencing |
| url | https://doi.org/10.1002/advs.202410110 |
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