Language
English
Publication Date
3-26-2025
Journal
Nature Communications
DOI
10.1038/s41467-025-58366-5
PMID
40140646
PMCID
PMC11947120
PubMedCentral® Posted Date
3-26-2025
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Glioblastoma, Humans, Neoplastic Stem Cells, Animals, Brain Neoplasms, Tumor Microenvironment, Mice, Cell Line, Tumor, Disease Progression, Cell Proliferation, Gene Expression Regulation, Neoplastic, Receptors, Notch, Xenograft Model Antitumor Assays, NF-kappa B, CNS cancer, Cancer stem cells, CNS cancer
Published Open-Access
yes
Recommended Citation
Lu, Chenfei; Kang, Tao; Zhang, Junxia; et al., "Combined Targeting of Glioblastoma Stem Cells of Different Cellular States Disrupts Malignant Progression" (2025). Faculty and Staff Publications. 3831.
https://digitalcommons.library.tmc.edu/baylor_docs/3831