Abstract
Therapeutic resistance remains a persistent challenge for patients with glioblastoma (GBM). Here, we report that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)-like cells in GBM, driving tumor resistance to cytotoxic treatment. Single-cell transcriptome analysis identified an EC-derived cell population that robustly expresses mesenchymal genes and stem cell-associated markers, suggesting that ECs undergo mesenchymal transformation and stemness-like activation in GBM microenvironment. Furthermore, we identified a c-Met-mediated axis that induces β-catenin phosphorylation at Ser675 and Wnt signaling activation, inducing multidrug resistance-associated protein-1 (MRP-1) expression and leading to EC stemness-like activation and chemoresistance. Last, genetic ablation of β-catenin in ECs overcome GBM tumor resistance to temozolomide (TMZ) chemotherapy in vivo. Combination of Wnt inhibition and TMZ chemotherapy eliminated tumor-associated ECs, inhibited GBM growth, and increased mouse survival. These findings identified a cell plasticity-based, microenvironment-dependent mechanism that controls tumor chemoresistance, and suggest that targeting Wnt/β-catenin-mediated EC transformation and stemness activation may overcome therapeutic resistance in GBM.
Single-Cell Transcriptome Analysis of CD34+ Stem Cell-Derived Myeloid Cells Infected With Human Cytomegalovirus
