Single-cell multi-omics sequencing uncovers region-specific plasticity of glioblastoma for complementary therapeutic targeting

Glioblastoma (GBM) cells are highly heterogeneous and invasive, leading to treatment resistance and relapse. However, the molecular regulation in and distal to tumors remains elusive. Here, we collected paired tissues from the tumor core (TC) and peritumoral brain (PTB) for integrated snRNA-seq and snATAC-seq analyses. Tumor cells infiltrating PTB from TC behave more like oligodendrocyte progenitor cells than astrocytes at the transcriptome level. Dual-omics analyses further suggest that the distal regulatory regions in the tumor genome and specific transcription factors are potential determinants of regional heterogeneity. Notably, while activator protein 1 (AP-1) is active in all GBM states, its activity declines from TC to PTB, with another transcription factor, BACH1, showing the opposite trend. Combined inhibition of AP-1 and BACH1 more efficiently attenuates the tumor progression in mice and prolongs survival than either single-target treatment. Together, our work reveals marked molecular alterations of infiltrated GBM cells and a synergy of combination therapy targeting intratumor heterogeneity in and distal to GBM.

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Publication Details

Journal
Science Advances
Published
2024-11-22
DOI
https://doi.org/10.1126/sciadv.adn4306
Citations
28
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
6.55
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article

Single-cell multi-omics sequencing uncovers region-specific plasticity of glioblastoma for complementary therapeutic targeting

Qian Sun, Weiwen Wang, Longqi Liu, Yeqing Huang et al.
28 citations
Science Advances
Single-cell and spatial transcriptomics
6.55
article

Single-cell multi-omics sequencing uncovers region-specific plasticity of glioblastoma for complementary therapeutic targeting

Qian Sun, Weiwen Wang, Longqi Liu, Yeqing Huang, Liang Chen, Hai‐Xi Sun, Junmin Wang, Tianbin Liu, Ying Gu, Daofeng Tian, Xuyi Lin, Fanen Yuan, Xin Wang, Yang Liu, Bo Wang, Baohui Liu, Haoran Lu, Qianxue Chen, Guiqian Huang
article en
28 citations

Abstract

Glioblastoma (GBM) cells are highly heterogeneous and invasive, leading to treatment resistance and relapse. However, the molecular regulation in and distal to tumors remains elusive. Here, we collected paired tissues from the tumor core (TC) and peritumoral brain (PTB) for integrated snRNA-seq and snATAC-seq analyses. Tumor cells infiltrating PTB from TC behave more like oligodendrocyte progenitor cells than astrocytes at the transcriptome level. Dual-omics analyses further suggest that the distal regulatory regions in the tumor genome and specific transcription factors are potential determinants of regional heterogeneity. Notably, while activator protein 1 (AP-1) is active in all GBM states, its activity declines from TC to PTB, with another transcription factor, BACH1, showing the opposite trend. Combined inhibition of AP-1 and BACH1 more efficiently attenuates the tumor progression in mice and prolongs survival than either single-target treatment. Together, our work reveals marked molecular alterations of infiltrated GBM cells and a synergy of combination therapy targeting intratumor heterogeneity in and distal to GBM.

Science AdvancesVol. 10(47)
BGI Group (China) (CN), Wuhan University (CN), Beijing Graphene Institute (CN), Renmin Hospital of Wuhan University (CN), China National GeneBank (CN), University of Chinese Academy of Sciences (CN), BGI Research (CN)
Good health and well-being
Openalex Percentile: Top 2%
Single-cell and spatial transcriptomics
6.55
DOIOpen Access PDFOpenAlex
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