Research ArticleBRAIN TUMOR

Wnt-mediated endothelial transformation into mesenchymal stem cell–like cells induces chemoresistance in glioblastoma

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Science Translational Medicine  26 Feb 2020:
Vol. 12, Issue 532, eaay7522
DOI: 10.1126/scitranslmed.aay7522

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Endothelial transformation in glioblastoma

Glioblastoma (GBM) is one of the most aggressive brain tumors. GBM is characterized by resistance to cytotoxic therapies and extensive vascular abnormalities. It has been recently shown that GBM-associated endothelial cells (ECs) might play a role in GBM cytotoxic resistance. Now, Huang et al. used in vitro cell cultures and in vivo models to investigate the role of ECs in pharmacoresistance. The authors showed that GBM-associated ECs acquired a mesenchymal stem cell–like phenotype, driving tumor resistance. Mesenchymal transformation was triggered by Wnt/β-catenin signaling activation in ECs. In a mouse model, β-catenin inhibition sensitized GBM to cytotoxic treatment, suggesting that combining cytotoxic therapy with Wnt signaling inhibition might overcome pharmacoresistance in GBM.

Abstract

Therapeutic resistance remains a persistent challenge for patients with malignant tumors. Here, we reveal that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)–like cells in glioblastoma (GBM), driving tumor resistance to cytotoxic treatment. Transcriptome analysis by RNA sequencing (RNA-seq) revealed 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.

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