GSC 2907 SRGN IP mass spectrometry

Glioblastoma (GBM) is a highly lethal primary malignant brain tumor. The high level of heterogeneity within GBM inevitably leads to treatment resistance and tumor recurrence. Glioblastoma stem cells (GSCs) contribute to the distinct properties of GBM through their contribution to therapeutic resilience. Here, we found that enhanced classical (CL) and mesenchymal (MES) transcriptional signatures were associated with poor patient prognosis. Through the integrated analyses of single-cell RNA sequencing and clinical datasets, we identified specific brain tumor targets, including MEOX2 for the CL subtype and SRGN for the MES subtype respectively. MEOX2 sustained the CL subtype signature and played a particular role in CL GSCs by activating Notch signaling. SRGN maintained the MES phenotype and regulated the NF-κB signaling by preventing NFKB1 from proteasomal degradation. Both genetic and pharmacologic treatments showed that CL GSCs were preferentially sensitive to the inhibition of MEOX2, while MES GSCs were more susceptible to SRGN. We further screend FDA-approved drugs with MEOX2 and SRGN targeting capabilities as candidates for further investigation. Combined CL and MES targeting demonstrated enhanced efficacy, both in vitro and in vivo. Collectively, our results elucidated the mechanism of GBM heterogeneity, and highlighted a therapeutic strategy for the elimination of heterogeneous cellular populations through combinatorial targeting of MEOX2 and SRGN in GSCs.