Phase Separation-Mediated SRF/P54nrb Transcription Complex Shapes the Vasculature Microenvironment via Upregulating OLFML3 in Glioblastoma

Abstract

Antiangiogenic therapy remains a challenging issue in the treatment of glioblastoma (GBM). Effective therapies are in urgent need to improve prognosis of GBM patients. The high heterogeneity of GBM is both the cause of its unavoidable therapeutic resistance and the result of extensive genomic dysregulation, of which abnormal transcription factor (TF) networks are recognized to be the culprit. Herein, based on the heterogeneity of GBM, we identified the key TF serum response factor (SRF), which is closely associated with the formation of the GBM vascular microenvironment, from a large-scale dataset. Mechanistically, the 133–240aa region of SRF binds to the transcriptional cofactor P54nrb and undergoes phase separation to form a transcription complex, which upregulates OLFML3 by binding to its enhancer and promoter regions. The secreted extracellular matrix (ECM) glycoprotein OLFML3 activates endothelial cells (ECs) by degrading and remodeling the ECM, releasing proangiogenic factors, promoting intercellular adhesion, and directly acting on ECs to promote angiogenesis. The hyperplasia vasculature, in turn, promotes the infiltration of M2-polarized macrophages, leading to the formation of an immunosuppressive microenvironment. This study comprehensively elucidates the pivotal role of SRF in GBM angiogenesis. Targeting the SRF/P54nrb/OLFML3 axis holds promise for developing novel antiangiogenic strategies to improve GBM treatment outcomes.

Keywords

glioblastoma / microenvironment / OLFML3 / P54nrb / phase separation / SRF

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