Modeling glioblastoma using genetically engineered brain organoids and spatial transcriptomics

10x Genomics and STEMCELL Technologies are excited to invite you to a webinar on the application of organoids and spatial transcriptomics in the study of Glioblastoma and development of a pre-clinical drug discovery platform.

Glioblastoma (GBM) is an aggressive, incurable form of brain cancer characterized by significant cellular heterogeneity due to interactions between tumor cell-intrinsic progenitor states and cell-extrinsic cues that promote rapid evolution. However, very few new therapeutic options for GBM have been developed in the last decade, highlighting the need for improved preclinical models. To address this need, we generated engineered GBM organoids (eGBOs) from genetically modified stem cells harboring mutations of both the Proneural and Mesenchymal subtypes of GBM. Using single-cell RNA sequencing (scRNAseq) and spatial transcriptomic analyses, we observed that GBM-associated mutations disrupt neurodevelopmental gene regulatory networks resulting in altered brain organoid morphology in vitro. Additionally, we found that transplantation of cells from eGBOs into mice results in tumors that recapitulate subtype-specific characteristics of human GBM tumors. Finally, we identified dynamic gene expression changes in developmental cell states underlying tumor progression using integrated single-cell transcriptomic data from eGBOs and patient GBM tumors. These single-cell and spatial transcriptomic analyses demonstrate that eGBOs can recapitulate GBM tumorigenesis and cellular heterogeneity found in patients. Further, this work provides an important validation of engineered cancer organoids as a human- relevant model that can enable future pre-clinical drug discovery of therapeutics designed to target patient-specific genetic backgrounds.