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

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.

Mesenchymal Transformation: The Rosetta Stone of Glioblastoma Pathogenesis and Therapy Resistance

“…[100] GBM-associated vascular ECs can also transform to a MES phenotype, increasing their ability to proliferate and migrate, ultimately promoting tumorigenesis and chemoresitance. [101][102][103] Aberrant vasculature in GBM microenvironment was observed when ECs acquired MES phenotype through c-Met signaling. [102] Mechanistically, c-Met can activate ETS-1/MMP-14 leading to vascular malfunction.…”

“…[102] Another study demonstrated that ECs acquired mesenchymal stem-like cell characteristics through c-Met/ -catenin/MRP-1-dependent mechanism, conferring chemoresistance in GBM. [103] Moreover, MES transformation of ECs can be induced by NF-B-dependent Snail expression under platelet-derived growth factor (PDGF) induction, while pharmacological and genetic inhibition of PDGF signaling sensitizes GBM to anti-VEGF/VEGFR therapy. [101] Hypoxia, a characteristic feature of solid tumors including GBM, can also induce mesenchymal transformation by regulating hypoxia-inducible factors (HIF) and proteins, controlling a vast array of gene expression related to mesenchymal transformation in various cancers.…”

Cross talk between mesenchymal and glioblastoma stem cells: Communication beyond controversies

“…79 Finally, the ability of GBM-associated endothelial cells to acquire a MSC-like phenotype in GBM TME also contributes to chemoresistance via the activation of Wnt/β-catenin axis and the multidrug resistance-associated protein-1. 102 Furthermore, the percentage of CD105 + /CD73 + /CD90 + GA-MSCs within tumor tissue of patients with high-grade glioma is inversely correlated with patient's overall survival. 103…”

Endothelial-to-Mesenchymal Transition in Cancer

“…Patients biopsies, cellular model (Fan et al, 2018) EVs (mir-92a) Angiogenesis Cellular model (Yamada et al, 2019) Pancreatic cancer nd Source of CAFs Patient biopsies, murine model (Zeisberg et al, 2007;Fan et al, 2019) Endoglin deficiency Metastasis Murine model (Anderberg et al, 2013) Lung cancer Radiation Resistance to radiotherapy Patients biopsies, murine model (Choi et al, 2018) Tumor secretome Resistance to chemotherapy Cellular model (Kim et al, 2019) Glioblastoma HGF/β-catenin Resistance to chemotherapy Patients biopsies, murine model (Huang et al, 2016(Huang et al, , 2020 PDGF Resistance to anti-angiogenic agents Murine model (Liu T. et al, 2018) Oral squamous carcinoma Wnt-5b Lymphangiogenesis Cellular model (Wang et al, 2017) Esophageal cancer TGF-β2-IL1β Source of CAFs Patients biopsies, cellular model (Nie et al, 2014) OPN, osteopontin; EV, extracellular vesicles; CAFs, cancer-associated fibroblasts; TGF-β, transforming growth factor-β; PDGF, platelet derived growth factor; nd, not determined. Toullec et al, 2018).…”