JMJD6-driven epigenetic activation of COL4A2 reprograms glioblastoma vascularization via integrin α1β1-dependent PI3K/MAPK signaling.

Abstract

Glioblastoma multiforme (GBM), the most aggressive primary brain malignancy in adults, is characterized by extensive vascularization and resistance to conventional anti-angiogenic therapies. In this study, through comprehensive integrative analyses of bulk RNA-seq and single-cell RNA-seq data, we identify COL4A2 as a critical orchestrator of vascularization in GBM. Elevated COL4A2 not only promotes epithelial-mesenchymal transition (EMT) in glioma cells, but also increases vascularization in GBM. Multi-omics profiling and mechanistic investigations reveal that aberrant expression of the anti-pause enhancer JMJD6 mediates the upregulation of COL4A2 in GBM. Furthermore, we demonstrate that COL4A2 promotes GBM vascularization by activating PI3K-AKT and MAPK-ERK signaling through interaction with ITGA1/ITGB1 receptors on tumor-associated endothelial cells (TECs). Pharmacological inhibition of the COL4A2-ITGA1/ITGB1 axis with obtustatin attenuates pro-angiogenic signaling, suppresses vascularization, and prolongs survival in orthotopic GBM models. Collectively, our findings establish JMJD6-driven COL4A2-ITGA1/ITGB1 axis as a novel anti-angiogenic therapeutic vulnerability, offering a promising strategy to disrupt TEC-tumor symbiosis and impede GBM progression.