Combined targeting of glioblastoma stem cells of different cellular states disrupts malignant progression

Glioblastoma (GBM) is the most lethal primary brain tumor with intra-tumoral hierarchy of glioblastoma stem cells (GSCs). The heterogeneity of GSCs within GBM inevitably leads to treatment resistance and tumor recurrence. Molecular mechanisms of different cellular state GSCs remain unclear. Here, we find that classical (CL) and mesenchymal (MES) GSCs are enriched in reactive immune region and high CL-MES signature informs poor prognosis in GBM. Through integrated analyses of GSCs RNA sequencing and single-cell RNA sequencing datasets, we identify specific GSCs targets, including MEOX2 for the CL GSCs and SRGN for the MES GSCs. MEOX2-NOTCH and SRGN-NFκB axes play important roles in promoting proliferation and maintaining stemness and subtype signatures of CL and MES GSCs, respectively. In the tumor microenvironment, MEOX2 and SRGN mediate the resistance of CL and MES GSCs to macrophage phagocytosis. Using genetic and pharmacologic approaches, we identify FDA-approved drugs targeting MEOX2 and SRGN. Combined CL and MES GSCs targeting demonstrates enhanced efficacy, both in vitro and in vivo. Our results highlighted a therapeutic strategy for the elimination of heterogeneous GSCs populations through combinatorial targeting of MEOX2 and SRGN in GSCs.

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Publication Details

Journal
Nature Communications
Published
2025-03-26
DOI
https://doi.org/10.1038/s41467-025-58366-5
Citations
16
Primary Topic
Glioma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
26.01
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article

Combined targeting of glioblastoma stem cells of different cellular states disrupts malignant progression

Wei Gao, Ningwei Zhao, Qianghu Wang, Nu Zhang et al.
16 citations
Nature Communications
Glioma Diagnosis and Treatment
26.01
article

Combined targeting of glioblastoma stem cells of different cellular states disrupts malignant progression

Wei Gao, Ningwei Zhao, Qianghu Wang, Nu Zhang, Daqi Li, Kailin Yang, Jiancheng Gao, Junxia Zhang, Zhumei Shi, Jeremy N. Rich, Qiulian Wu, Xiuxing Wang, Yun Chen, Chenfei Lu, Yangqing Li, Chunsheng Kang, Deobrat Dixit, Hui Yang, Sameer Agnihotri, Danling Gu, Jianghong Man, Zhe Zhu, Stephen C. Mack, Ying‐Mei Lu, Linjie Zhao, Ryan C. Gimple, Danyang Shan, Xu Qian, Zhibin Hu, Fan Lin, Weiwei Tao, Ming Lu, Yang Liu, Qian Zhang, Ning Liu, Jing Ji, Wei Zhang, Michael D. Taylor, Junlei Yang, Hao You, Tao Kang, Chaojun Li, Fan Xiao, Kefan Song, Zhixin Qiu, Qiankun Lin, Yong-ping You
article en
16 citations

Abstract

Glioblastoma (GBM) is the most lethal primary brain tumor with intra-tumoral hierarchy of glioblastoma stem cells (GSCs). The heterogeneity of GSCs within GBM inevitably leads to treatment resistance and tumor recurrence. Molecular mechanisms of different cellular state GSCs remain unclear. Here, we find that classical (CL) and mesenchymal (MES) GSCs are enriched in reactive immune region and high CL-MES signature informs poor prognosis in GBM. Through integrated analyses of GSCs RNA sequencing and single-cell RNA sequencing datasets, we identify specific GSCs targets, including MEOX2 for the CL GSCs and SRGN for the MES GSCs. MEOX2-NOTCH and SRGN-NFκB axes play important roles in promoting proliferation and maintaining stemness and subtype signatures of CL and MES GSCs, respectively. In the tumor microenvironment, MEOX2 and SRGN mediate the resistance of CL and MES GSCs to macrophage phagocytosis. Using genetic and pharmacologic approaches, we identify FDA-approved drugs targeting MEOX2 and SRGN. Combined CL and MES GSCs targeting demonstrates enhanced efficacy, both in vitro and in vivo. Our results highlighted a therapeutic strategy for the elimination of heterogeneous GSCs populations through combinatorial targeting of MEOX2 and SRGN in GSCs.

Nature CommunicationsVol. 16(1)
St. Jude Children's Research Hospital (US), Nanjing University of Chinese Medicine (CN), Cleveland Clinic (US), Sun Yat-sen University (CN), Baylor College of Medicine (US), Capital Medical University (CN), Huazhong Agricultural University (CN), Fudan University (CN), Columbia University Irving Medical Center (US), Tianjin Medical University General Hospital (CN), Beijing Tian Tan Hospital (CN), Ministry of Education (KR), Zhongshan Hospital (CN), National Center of Biomedical Analysis (CN), Jiangsu Cancer Hospital (CN), UPMC Hillman Cancer Center (US), The First Affiliated Hospital, Sun Yat-sen University (CN), University of Pittsburgh Medical Center (US), Children's Cancer Center (US), Jiangsu Province Hospital (CN), Huashan Hospital (CN), State Key Laboratory of Medical Neurobiology, Nanjing Medical University (CN)
Good health and well-being
Openalex Percentile: Top 0%
Glioma Diagnosis and Treatment
26.01
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