Journal article
Combined targeting of glioblastoma stem cells of different cellular states disrupts malignant progression
Nature communications, Vol.16(1), 2974
03/26/2025
DOI: 10.1038/s41467-025-58366-5
PMCID: PMC11947120
PMID: 40140646
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.
Details
- Title: Subtitle
- Combined targeting of glioblastoma stem cells of different cellular states disrupts malignant progression
- Creators
- Chenfei Lu - Nanjing Medical UniversityTao Kang - Nanjing Medical UniversityJunxia Zhang - Nanjing Medical UniversityKailin Yang - Cleveland ClinicYang Liu - Nanjing University of Chinese MedicineKefan Song - Nanjing Medical UniversityQiankun Lin - Nanjing Medical UniversityDeobrat Dixit - University of Pittsburgh Medical CenterRyan C Gimple - Cleveland ClinicQian Zhang - Nanjing Medical UniversityZhumei Shi - Nanjing Medical UniversityXiao Fan - Jiangsu Province HospitalQiulian Wu - University of Pittsburgh Medical CenterDaqi Li - Nanjing Medical UniversityDanyang Shan - Nanjing Medical UniversityJiancheng Gao - Nanjing Medical UniversityDanling Gu - Nanjing Medical UniversityHao You - Nanjing Medical UniversityYangqing Li - Nanjing Medical UniversityJunlei Yang - Nanjing Medical UniversityLinjie Zhao - University of Pittsburgh Medical CenterZhixin Qiu - Fudan UniversityHui Yang - Fudan UniversityNingwei Zhao - Nanjing University of Chinese MedicineWei Gao - Nanjing Medical UniversityWeiwei Tao - Huazhong Agricultural UniversityYingmei Lu - Nanjing Medical UniversityYun Chen - Nanjing Medical UniversityJing Ji - Nanjing Medical UniversityZhe Zhu - Columbia University Irving Medical CenterChunsheng Kang - Tianjin Medical University General HospitalJianghong Man - National Center of Biomedical AnalysisSameer Agnihotri - University of Pittsburgh Medical CenterQianghu Wang - Nanjing Medical UniversityFan Lin - Nanjing Medical UniversityXu Qian - Nanjing Medical UniversityStephen C Mack - St. Jude Children's Research HospitalZhibin Hu - Nanjing Medical UniversityChaojun Li - Nanjing Medical UniversityMichael D Taylor - Baylor College of MedicineNing Liu - Nanjing Medical UniversityNu Zhang - Sun Yat-sen UniversityMing Lu - Nanjing Medical UniversityYongping You - Nanjing Medical UniversityJeremy N Rich - University of Pittsburgh Medical CenterWei Zhang - Beijing Tian Tan HospitalXiuxing Wang - Jiangsu Cancer Hospital
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.16(1), 2974
- DOI
- 10.1038/s41467-025-58366-5
- PMID
- 40140646
- PMCID
- PMC11947120
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- NATURE PORTFOLIO
- Grant note
- The National Natural Science Foundation of China (82072779 to X.W., 82272651 and 81974389 to Y.Y., 82273477 to N.L.) Jiangsu Province Capability Improvement Project through Science, Technology and Education (ZDXK202225 to Y.Y.) Postdoctoral Fellowship Prog: 82072779, 82272651, 81974389, 82273477 National Natural Science Foundation of China: ZDXK202225 Jiangsu Province Capability Improvement Project through Science, Technology and Education: GZC20231157 Postdoctoral Fellowship Program of CPSF
We thank the Nanjing Medical University Analysis Center for help with FACS. We thank the C. Huang for technical assistance for HPLC. This work was supported by the National Natural Science Foundation of China (82072779 to X.W., 82272651 and 81974389 to Y.Y., 82273477 to N.L.), Jiangsu Province Capability Improvement Project through Science, Technology and Education (ZDXK202225 to Y.Y.) and Postdoctoral Fellowship Program of CPSF (GZC20231157 to CF.L.).
- Language
- English
- Date published
- 03/26/2025
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984802193102771
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