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

Chenfei Lu, Tao Kang, Junxia Zhang, Kailin Yang, Yang Liu, Kefan Song, Qiankun Lin, Deobrat Dixit, Ryan C. Gimple, Qian Zhang, Zhumei Shi, Xiao Fan, Qiulian Wu, Daqi Li, Danyang Shan, Jiancheng Gao, Danling Gu, Hao You, Yangqing Li, Junlei Yang, Linjie Zhao, Zhixin Qiu, Hui Yang, Ningwei Zhao, Wei Gao, Weiwei Tao, Yingmei Lu, Yun Chen, Jing Ji, Zhe Zhu, Chunsheng Kang, Jianghong Man, Sameer Agnihotri, Qianghu Wang, Fan Lin, Xu Qian, Stephen C. Mack, Zhibin Hu, Chaojun Li, Michael D. Taylor, Ning Liu, Nu Zhang, Ming Lu, Yongping You (), Jeremy N. Rich (), Wei Zhang () and Xiuxing Wang ()
Additional contact information
Chenfei Lu: The First Affiliated Hospital of Nanjing Medical University
Tao Kang: Nanjing Medical University
Junxia Zhang: The First Affiliated Hospital of Nanjing Medical University
Kailin Yang: Cleveland Clinic
Yang Liu: Nanjing University of Chinese Medicine
Kefan Song: The First Affiliated Hospital of Nanjing Medical University
Qiankun Lin: Nanjing Medical University
Deobrat Dixit: University of Pittsburgh Medical Center Hillman Cancer Center
Ryan C. Gimple: Cleveland Clinic
Qian Zhang: Nanjing Medical University
Zhumei Shi: The First Affiliated Hospital of Nanjing Medical University
Xiao Fan: The First Affiliated Hospital of Nanjing Medical University
Qiulian Wu: University of Pittsburgh Medical Center Hillman Cancer Center
Daqi Li: Nanjing Medical University
Danyang Shan: Nanjing Medical University
Jiancheng Gao: The First Affiliated Hospital of Nanjing Medical University
Danling Gu: Nanjing Medical University
Hao You: Nanjing Medical University
Yangqing Li: Nanjing Medical University
Junlei Yang: Nanjing Medical University
Linjie Zhao: University of Pittsburgh Medical Center Hillman Cancer Center
Zhixin Qiu: Fudan University
Hui Yang: Fudan University
Ningwei Zhao: Affiliated Hospital of Nanjing University of Chinese Medicine
Wei Gao: Nanjing Medical University
Weiwei Tao: Huazhong Agricultural University
Yingmei Lu: Nanjing Medical University
Yun Chen: Nanjing Medical University
Jing Ji: The First Affiliated Hospital of Nanjing Medical University
Zhe Zhu: Columbia University Irving Medical Center
Chunsheng Kang: Tianjin Medical University General Hospital
Jianghong Man: National Center of Biomedical Analysis
Sameer Agnihotri: University of Pittsburgh Medical Center Hillman Cancer Center
Qianghu Wang: Nanjing Medical University
Fan Lin: Nanjing Medical University
Xu Qian: Nanjing Medical University
Stephen C. Mack: St. Jude Children’s Research Hospital
Zhibin Hu: Nanjing Medical University
Chaojun Li: Nanjing Medical University
Michael D. Taylor: Baylor College of Medicine
Ning Liu: The First Affiliated Hospital of Nanjing Medical University
Nu Zhang: Guangzhou
Ming Lu: Nanjing Medical University
Yongping You: The First Affiliated Hospital of Nanjing Medical University
Jeremy N. Rich: University of Pittsburgh Medical Center Hillman Cancer Center
Wei Zhang: Capital Medical University
Xiuxing Wang: The First Affiliated Hospital of Nanjing Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58366-5

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