Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice
Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice
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DOI：
10.1126/science.aaw9886
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发表时间：
2019-11-22
期刊：
影响因子：
56.9
通讯作者：
Halder, Georg
中科院分区：
文献类型：
--
作者：
Moya, Ivan M.;Castaldo, Stephanie A.;Halder, Georg
Hippo信号通路及其两个下游效应子雅普和TAZ转录共激活因子是实验模型中肿瘤生长的驱动因子。研究小鼠模型，我们表明，雅普和TAZ也可以发挥抑瘤功能。我们发现肝肿瘤周围的正常肝细胞显示雅普和TAZ的激活，并且在这些肿瘤周围肝细胞中缺失雅普和TAZ加速肿瘤生长。相反，实验性肿瘤周围肝细胞中雅普的过度活化引发原发性肝肿瘤和黑色素瘤衍生的肝转移的消退。此外，在野生型肝脏中生长的肿瘤细胞需要雅普和TAZ才能生存，而那些被雅普和Taz缺陷肝细胞包围的肿瘤细胞不依赖于雅普和TAZ。因此，肿瘤细胞存活取决于肿瘤细胞及其周围组织中雅普和TAZ的相对活性，表明雅普和TAZ通过细胞竞争机制消除肿瘤细胞。
The Hippo signaling pathway and its two downstream effectors, the YAP and TAZ transcriptional coactivators, are drivers of tumor growth in experimental models. Studying mouse models, we show that YAP and TAZ can also exert a tumor-suppressive function. We found that normal hepatocytes surrounding liver tumors displayed activation of YAP and TAZ and that deletion of Yap and Taz in these peritumoral hepatocytes accelerated tumor growth. Conversely, experimental hyperactivation of YAP in peritumoral hepatocytes triggered regression of primary liver tumors and melanoma-derived liver metastases. Furthermore, whereas tumor cells growing in wild-type livers required YAP and TAZ for their survival, those surrounded by Yap- and Taz-deficient hepatocytes were not dependent on YAP and TAZ. Tumor cell survival thus depends on the relative activity of YAP and TAZ in tumor cells and their surrounding tissue, suggesting that YAP and TAZ act through a mechanism of cell competition to eliminate tumor cells.