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.

中文翻译：

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Wnt介导的内皮细胞转化为间充质干细胞样细胞诱导胶质母细胞瘤的化学耐药性。

对于恶性肿瘤患者，治疗抗性仍然是一项持续的挑战。在这里，我们揭示了内皮细胞（EC）获得转化为胶质母细胞瘤（GBM）中的间充质干细胞（MSC）样细胞，从而驱动肿瘤对细胞毒性治疗的抵抗力。通过RNA测序（RNA-seq）进行的转录组分析显示，ECs在GBM微环境中经历了间充质转化和干样激活。此外，我们确定了一个c-Met介导的轴，该轴在Ser675和Wnt信号激活时诱导β-catenin磷酸化，诱导多药耐药相关蛋白1（MRP-1）的表达并导致EC干样激活和化学抗性。最后，ECs中的β-catenin的基因消融克服了GBM体内对替莫唑胺（TMZ）化疗的耐药性。Wnt抑制和TMZ化疗的结合消除了肿瘤相关的EC，抑制了GBM的生长，并提高了小鼠的存活率。这些发现确定了一种基于细胞可塑性，微环境依赖性的机制来控制肿瘤的化学耐药性，并表明靶向Wnt /β-catenin介导的EC转化和干性激活可以克服GBM中的治疗耐药性。