很有意思的研究。颠覆对YAP/TAZ在肿瘤中的作用的传统认知。
Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice
Science ( IF 41.037 ) Pub Date : 2019-11-22 *, DOI: *10.1126/science.aaw9886
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.
这项发现令人惊讶，因为YAP和TAZ通常是在不同人类癌细胞中高表达，这些基因能启动肿瘤细胞的增殖和存活。文章第一作者Iván Moya表示：“传统观点认为它们是致癌基因，但是却发现具有抗肿瘤功能，这完全改变了我们对致癌基因，以及它们在正常组织中的功能的看法。”
肝肿瘤细胞对YAP/TAZ的依赖性并不是绝对的，而是与邻近肝细胞YAP/TAZ的水平有关。因此，YAP/TAZ在肿瘤细胞中的主要作用是提高其竞争适应度，保护其免受周围实质的抑瘤作用。
Key experiment results:
YAP在肿瘤细胞中的表达水平与在胆管和内皮细胞中的表达水平一样高，而YAP在肿瘤周围的正常表达是由肿瘤引起的，而不是由潜在的肝脏疾病引起的。YAP/TAZ在瘤周肝细胞中被激活。
YAP/TAZ在癌周肝细胞中的一种非自主抑制肿瘤生长的意外活性。
瘤周肝细胞异位YAP激活足以诱导肿瘤消退。
肿瘤的清除不是由癌周肝细胞过度增殖引起的，而是由YAP/TAZ激活所驱动的一种特异性作用。、
癌周肝细胞中YAP/TAZ的激活可触发肿瘤细胞的非凋亡性程序性死亡，BCL2的过度表达可阻止肿瘤细胞的非凋亡性程序性死亡。
因此，当被WT肝细胞包围时，YAP和TAZ是维持N-Akt肿瘤的必要条件。
N-Akt肿瘤细胞需要YAP/TAZ才能存活，但只有当被WT肝细胞包围时。如果WT肝细胞周围细胞也没有YAP/TAZ, N-Akt肿瘤细胞也不需要YAP/TAZ活性。
瘤周肝细胞的YAP活化足以消除肝癌。
除了肝癌，YAP激活的肝细胞可以抑制高度侵袭性的NRAS突变体黑色素瘤细胞。
肝肿瘤细胞对YAP/TAZ的依赖性并不是绝对的，而是与邻近肝细胞YAP/TAZ的水平有关。因此，YAP/TAZ在肿瘤细胞中的主要作用是提高其竞争适应度，保护其免受周围实质的抑瘤作用。
跟传统的认知不同，系统性抑制YAP/TAZ可能具有不良的促癌作用。
The tumor suppression effect described here is reminiscent of “cell competition,” a phenomenon originally described in Drosophila but recently also observed in mammalian systems (21, 22). During competition, intact viable cells are eliminated from a tissue when they are adjacent to cells that have higher fitness (referred to as winner and loser cells) (21, 22). Notably, winner or loser status is not an inherent property of a cell but can change depending upon alterations in the neighboring cells
可以不可以这么理解： 细胞之间都是互相掐架， YAP/TAZ代表了某种力量，力量的大就容易打赢呢。那这个力量到底是什么呢？**-代谢优势， 抗凋亡，机械力。。。。。
肝脏里面这样，其他组织呢?
TAZ/YAP 如此， 其他的抗癌、抑癌基因呢？
肿瘤就是一种"Cell competiton" 吗？？
