Modeling the precise interaction of glioblastoma with human brain region-specific organoids

Qi Fan; Hanze Wang; Tianyi Gu; Huihui Liu; Peng Deng; Bo Li; Hui Yang; Ying Mao; Zhicheng Shao

doi:10.1016/j.isci.2024.109111

Modeling the precise interaction of glioblastoma with human brain region-specific organoids

iScience. 2024 Feb 5;27(3):109111. doi: 10.1016/j.isci.2024.109111. eCollection 2024 Mar 15.

Authors

Qi Fan¹, Hanze Wang², Tianyi Gu³, Huihui Liu¹, Peng Deng², Bo Li², Hui Yang^{2

4

5}, Ying Mao^{2

4

5}, Zhicheng Shao¹

Affiliations

¹ Institutes for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institute of Pediatrics, National Children's Medical Center, Children's Hospital, Fudan University, Shanghai, China.
² Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China.
³ Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai 201203, China.
⁴ National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai 200040, China.
⁵ Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai 200040, China.

Abstract

Glioblastoma is a highly aggressive malignant tumor of the central nervous system, but the interaction between glioblastoma and different types of neurons remains unclear. Here, we established a co-culture model in vitro using 3D printed molds with microchannels, in which glioblastoma organoids (GB), dorsal forebrain organoids (DO, mainly composed of excitatory neurons), and ventral forebrain organoids (VO, mainly composed of inhibitory neurons) were assembled. Our results indicate that DO has a greater impact on altered gene expression profiles of GB, resulting in increased invasive potential. GB cells preferentially invaded DO along axons, whereas this phenomenon was not observed in VO. Furthermore, GB cells selectively inhibited neurite outgrowth in DOs and reduced the expression of the vesicular GABA transporter (VGAT), leading to neuronal hyperexcitability. By revealing how glioblastoma interacts with brain cells, our study provides a more comprehensive understanding of this disease.

Keywords: Microenvironment; Molecular biology; Neuroscience; Omics; Techniques in neuroscience; Transcriptomics.