Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Department of Biology, Oberlin College, Oberlin, OH 44074, USA.
Sci Transl Med. 2020 Feb 26;12(532). doi: 10.1126/scitranslmed.aay7522.
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 Ser 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.
治疗抵抗仍然是恶性肿瘤患者面临的一个持续挑战。在这里，我们揭示了内皮细胞（ECs）在胶质母细胞瘤（GBM）中获得向间充质干细胞（MSC）样细胞的转化，从而驱动肿瘤对细胞毒性治疗的抵抗。通过 RNA 测序（RNA-seq）的转录组分析显示，ECs 在 GBM 微环境中经历间充质转化和干细胞样激活。此外，我们鉴定出一个 c-Met 介导的轴，诱导β-连环蛋白在丝氨酸的磷酸化和 Wnt 信号的激活，诱导多药耐药相关蛋白 1（MRP-1）的表达，并导致 EC 干细胞样激活和化疗耐药。最后，在体内，通过基因敲除 EC 中的β-连环蛋白来克服 GBM 对替莫唑胺（TMZ）化疗的耐药性。Wnt 抑制与 TMZ 化疗的联合使用消除了肿瘤相关的 ECs，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和微环境依赖性的机制，控制肿瘤的化疗耐药性，并表明靶向 Wnt/β-连环蛋白介导的 EC 转化和干细胞样激活可能克服 GBM 中的治疗抵抗。
