YAP/TAZ inhibition reduces metastatic potential of Ewing sarcoma cells.
YAP/TAZ inhibition reduces metastatic potential of Ewing sarcoma cells.
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DOI：
10.1038/s41389-020-00294-8
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发表时间：
2021-01-08
期刊：
影响因子：
6.2
通讯作者：
Kovar H
中科院分区：
文献类型：
--
作者：
Bierbaumer L;Katschnig AM;Radic-Sarikas B;Kauer MO;Petro JA;Högler S;Gurnhofer E;Pedot G;Schäfer BW;Schwentner R;Mühlbacher K;Kromp F;Aryee DNT;Kenner L;Uren A;Kovar H
尤文肉瘤(EWS)是一种以EWS-FLI1融合癌蛋白为特征的高度转移性骨癌。EWS细胞是典型的高度可塑性的细胞，根据EWS-FLI1的波动在不同的功能状态之间切换。EWS-FLI1高表达细胞增殖，而EWS-FLI1低表达细胞具有迁移和侵袭性。最近，我们报道了RhoA和Hippo信号的效应者MRTFB和TEAD在低EWS-FLI1上激活，协调EWS迁移基因表达计划的关键步骤。TEAD及其共激活因子YAP和TAZ在癌症中通常过表达，提供了有吸引力的治疗靶点。我们发现，在迁移性EWS-FLI1低状态下，TAZ水平升高，并与EWS患者的不良预后相关。我们检测了有效的YAP/TAZ/TEAD复合抑制剂维替普芬对EWS细胞体外迁移和体内转移的影响。维替普芬抑制EWS-FLI1调控的细胞骨架基因的表达，参与肌动蛋白向细胞外基质的信号传递，有效地阻止F-肌动蛋白和焦点黏附组装，并在亚微摩尔浓度下抑制EWS细胞的迁移。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和延迟的肺转移。这些数据表明，抑制YAP/TAZ通路可能阻止EWS细胞的扩散和转移，为进一步开发YAP/TAZ抑制剂用于EWS治疗提供了临床前证据。
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-FLI1high cells proliferate, EWS-FLI1low 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-FLI1low 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.
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影响因子：
--
作者：
Herrero-Martin D;Fourtouna A;Niedan S;Riedmann LT;Schwentner R;Aryee DN
通讯作者：
Aryee DN
影响因子：
4.8
作者：
Donohue, Elizabeth;Tovey, Andrew;Roberge, Michel
通讯作者：
Roberge, Michel
影响因子：
3.2
作者：
Arjonen, Antti;Kaukonen, Riina;Ivaska, Johanna
通讯作者：
Ivaska, Johanna
影响因子：
6.4
作者：
Brinkrolf, Peter;Landmeier, Silke;Rossig, Claudia
通讯作者：
Rossig, Claudia
影响因子：
6.6
作者：
Crawford, James J.;Bronner, Sarah M.;Zbieg, Jason R.
通讯作者：
Zbieg, Jason R.