Rap1b promotes glioma growth and stemness via regulation of Notch1 and VEGFR2 signaling pathways.

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by rapid growth, thereby resistance, and enrichment of glioma stem-like cells (GSCs). Despite advances in understanding GBM biology, the molecular mechanisms sustaining tumorigenesis and stemness remain incompletely defined. We investigated the role of Rap1b, a small GTPase, in glioma progression using patient-derived datasets, GBM cell lines, GSC cultures, and a xenograft mouse model. Functional assays, immunoblotting, immunofluorescence, qRT-PCR, and in vivo tumor growth analysis were performed. Rap1b was found to be highly expressed in GSCs and played a central role in regulating Notch1 and VEGFR2 signaling. Functionally, Rap1b promoted GBM cell proliferation and invasion by inhibiting apoptosis and promoting cell cycle progression beyond the G2/M checkpoint. Furthermore, Rap1b regulated the expression of key stemness markers CD133, ALDH1, and SOX2, contributing to the maintenance of GSC phenotypes. Clinically, elevated Rap1b expression correlated with higher tumor grade and poorer overall survival in glioma patients. Mechanistically, Rap1b translocated into the nucleus upon activation, suggesting a possible role as a transcriptional regulator. In vivo, Rap1b downregulation significantly reduced glioma growth in a nude mouse xenograft model. Our findings uncover a previously underappreciated role of Rap1b in promoting glioma cell proliferation, stemness, and tumor growth through modulation of Notch and VEGFR2 pathways. These results suggest that Rap1b may serve as a novel therapeutic target in glioblastoma by disrupting critical signaling networks that sustain tumor progression and stem cell-like features.