Ewing sarcoma (EwS) is a highly metastatic bone cancer characterized by the ETS fusion oncoprotein EWS-FLI1. EwS cells are phenotypically highly plastic and switch between functionally distinct cell states dependent on EWS-FLI1 fluctuations. Whereas EWS-FLI1^high cells proliferate, EWS-FLI1^low cells are migratory and invasive. Recently, we reported activation of MRTFB and TEAD, effectors of RhoA and Hippo signalling, upon low EWS-FLI1, orchestrating key steps of the EwS migratory gene expression program. TEAD and its co-activators YAP and TAZ are commonly overexpressed in cancer, providing attractive therapeutic targets. We find TAZ levels to increase in the migratory EWS-FLI1^low state and to associate with adverse prognosis in EwS patients. We tested the effects of the potent YAP/TAZ/TEAD complex inhibitor verteporfin on EwS cell migration in vitro and on metastasis in vivo. Verteporfin suppressed expression of EWS-FLI1 regulated cytoskeletal genes involved in actin signalling to the extracellular matrix, effectively blocked F-actin and focal-adhesion assembly and inhibited EwS cell migration at submicromolar concentrations. In a mouse EwS xenograft model, verteporfin treatment reduced relapses at the surgical site and delayed lung metastasis. These data suggest that YAP/TAZ pathway inhibition may prevent EwS cell dissemination and metastasis, justifying further preclinical development of YAP/TAZ inhibitors for EwS treatment.

尤文肉瘤 (EwS) 是一种以 ETS 融合癌蛋白 EWS-FLI1 为特征的高度转移性骨癌。EwS 细胞在表型上具有高度的可塑性，并且依赖于 EWS-FLI1 波动在功能不同的细胞状态之间切换。而 EWS-FLI1^高细胞增殖，EWS-FLI1^低细胞是迁移和侵入性的。最近，我们报道了在低 EWS-FLI1 时激活 MRTFB 和 TEAD，即 RhoA 和 Hippo 信号传导的效应器，协调 EwS 迁移基因表达程序的关键步骤。TEAD 及其共激活剂 YAP 和 TAZ 通常在癌症中过度表达，从而提供有吸引力的治疗靶点。我们发现 TAZ 水平在迁移 EWS-FLI1^低点增加状态并与 EwS 患者的不良预后相关。我们测试了有效的 YAP/TAZ/TEAD 复合物抑制剂维替泊芬对体外 EwS 细胞迁移和体内转移的影响。Verteporfin 抑制 EWS-FLI1 调节的细胞骨架基因的表达，这些基因参与肌动蛋白信号传导至细胞外基质，有效阻断 F-肌动蛋白和焦点粘附组装，并在亚微摩尔浓度下抑制 EwS 细胞迁移。在小鼠 EwS 异种移植模型中，维替泊芬治疗减少了手术部位的复发并延迟了肺转移。这些数据表明，YAP/TAZ 通路抑制可能会阻止 EwS 细胞传播和转移，这证明了进一步开发用于 EwS 治疗的 YAP/TAZ 抑制剂的临床前开发。