Spatial transcriptomics reveals niche-specific enrichment and vulnerabilities of radial glial stem-like cells in malignant gliomas

Yanming Ren, Zongyao Huang, Lingling Zhou, Peng Xiao, Junwei Song, Ping He, Chuanxing Xie, Ran Zhou, Menghan Li, Xiangqun Dong, Qing Mao, Chao You, Jianguo Xu, Yanhui Liu, Zhigang Lan, Tiejun Zhang, Qi Gan, Yuan Yang, Tengyun Chen, Bowen Huang, Xiang Yang, Anqi Xiao, Yun Ou, Zhengzheng Su, Lu Chen (), Yan Zhang (), Yan Ju (), Yuekang Zhang () and Yuan Wang ()
Additional contact information
Yanming Ren: Sichuan University
Zongyao Huang: Sichuan University
Lingling Zhou: Sichuan University
Peng Xiao: Sichuan University
Junwei Song: Sichuan University
Ping He: Sichuan University
Chuanxing Xie: Sichuan University
Ran Zhou: Sichuan University
Menghan Li: Sichuan University
Xiangqun Dong: Sichuan University
Qing Mao: Sichuan University
Chao You: Sichuan University
Jianguo Xu: Sichuan University
Yanhui Liu: Sichuan University
Zhigang Lan: Sichuan University
Tiejun Zhang: Sichuan University
Qi Gan: Sichuan University
Yuan Yang: Sichuan University
Tengyun Chen: Sichuan University
Bowen Huang: Sichuan University
Xiang Yang: Sichuan University
Anqi Xiao: Sichuan University
Yun Ou: Sichuan University
Zhengzheng Su: Sichuan University
Lu Chen: Sichuan University
Yan Zhang: Sichuan University
Yan Ju: Sichuan University
Yuekang Zhang: Sichuan University
Yuan Wang: Sichuan University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Diffuse midline glioma-H3K27M mutant (DMG) and glioblastoma (GBM) are the most lethal brain tumors that primarily occur in pediatric and adult patients, respectively. Both tumors exhibit significant heterogeneity, shaped by distinct genetic/epigenetic drivers, transcriptional programs including RNA splicing, and microenvironmental cues in glioma niches. However, the spatial organization of cellular states and niche-specific regulatory programs remain to be investigated. Here, we perform a spatial profiling of DMG and GBM combining short- and long-read spatial transcriptomics, and single-cell transcriptomic datasets. We identify clinically relevant transcriptional programs, RNA isoform diversity, and multi-cellular ecosystems across different glioma niches. We find that while the tumor core enriches for oligodendrocyte precursor-like cells, radial glial stem-like (RG-like) cells are enriched in the neuron-rich invasive niche in both DMG and GBM. Further, we identify niche-specific regulatory programs for RG-like cells, and functionally confirm that FAM20C mediates invasive growth of RG-like cells in a neuron-rich microenvironment in a human neural stem cell derived orthotopic DMG model. Together, our results provide a blueprint for understanding the spatial architecture and niche-specific vulnerabilities of DMG and GBM.

Date: 2023
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DOI: 10.1038/s41467-023-36707-6

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