Integrative Single‐Cell Analysis Reveals Targetable Vacuole Membrane Protein 1‐Mediated Mechanism of Tumor Angiogenesis in Glioblastoma

ABSTRACT Vacuole membrane Protein 1 (VMP1) is widely known to be an important mediator in the formation of autophagosomes, playing a crucial role in macroautophagic processes. Emerging evidence suggests that VMP1 may have context‐dependent functions across diverse cancer types and different tumor microenvironments, both within the context of autophagy and beyond. Here, using glioblastoma as a cancer model, we found that VMP1 can promote tumor growth independent of its autophagic functions. We observed significant upregulation of VMP1 in glioblastoma, which was correlated with poorer prognosis, and its ability to promote tumor growth without altering autophagic flux. Bulk, single‐cell, and spatial transcriptomics analyses revealed that the pro‐angiogenic markers were enriched in glioblastomas with high VMP1 expression. We further validated that overexpression of VMP1 would enhance angiogenesis through VEGFA‐VEGFR2 signaling‐mediated activation in endothelial cells. Treatment with bevacizumab, a monoclonal antibody against VEGFA, significantly inhibited VMP1‐driven tumor growth and prolonged survival in mice. Our study thus uncovered non‐autophagic functions of VMP1 as an important mediator in glioblastoma angiogenesis with the potential for therapeutic targeting.