YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression.
YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression.
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DOI：
10.1016/j.celrep.2019.03.021
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发表时间：
2019-12-03
期刊：
影响因子：
8.8
通讯作者：
Mao J
中科院分区：
文献类型：
--
作者：
Li H;Li Q;Dang K;Ma S;Cotton JL;Yang S;Zhu LJ;Deng AC;Ip YT;Johnson RL;Wu X;Punzo C;Mao J
葡萄膜黑色素瘤(UM)是最常见的眼部恶性肿瘤，以GNAQ/11突变为特征。HIPPO/YAP和RAS/丝裂原活化蛋白激酶(Ras/MAPK)是Q类(GαQ/11)介导的G蛋白α亚基下游的两条重要信号通路，尽管它们在体内是否以及如何参与UM的发生尚不清楚。在这里，我们采用了一种基于腺相关病毒(AAV)的眼部注射方法，将Cre重组酶直接转移到小鼠葡萄膜束中，并证明了Lats1/2激酶抑制葡萄膜黑素细胞中特异性的UM形成。我们发现，YAP的基因激活足以启动UM，但不是Kras。我们发现，Lats1/2缺失诱导的YAP/TAZ激活与Kras协同作用，通过下游转录增强促进UM进展。此外，YAP/TAZ和RAS/MAPK的双重抑制可协同抑制人UM细胞的致癌生长。我们的数据强调了LATS-YAP/TAZ在UM体内发生和发展中的功能意义，并建议联合抑制YAP/TAZ和RAS/MAPK作为UM的一种新的治疗策略。
Uveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations. Hippo/YAP and Ras/mitogen-activated protein kinase (MAPK) emerge as two important signaling pathways downstream of G protein alpha subunits of the Q class (GαQ/11)-mediated transformation, although whether and how they contribute to UM genesis in vivo remain unclear. Here, we adapt an adeno-associated virus (AAV)-based ocular injection method to directly deliver Cre recombinase into the mouse uveal tract and demonstrate that Lats1/2 kinases suppress UM formation specifically in uveal melanocytes. We find that genetic activation of YAP, but not Kras, is sufficient to initiate UM. We show that YAP/TAZ activation induced by Lats1/2 deletion cooperates with Kras to promote UM progression via downstream transcriptional reinforcement. Furthermore, dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress oncogenic growth of human UM cells. Our data highlight the functional significance of Lats-YAP/TAZ in UM initiation and progression in vivo and suggest combination inhibition of YAP/TAZ and Ras/MAPK as a new therapeutic strategy for UM.
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影响因子：
64.5
作者：
Kapoor A;Yao W;Ying H;Hua S;Liewen A;Wang Q;Zhong Y;Wu CJ;Sadanandam A;Hu B;Chang Q;Chu GC;Al-Khalil R;Jiang S;Xia H;Fletcher-Sananikone E;Lim C;Horwitz GI;Viale A;Pettazzoni P;Sanchez N;Wang H;Protopopov A;Zhang J;Heffernan T;Johnson RL;Chin L;Wang YA;Draetta G;DePinho RA
通讯作者：
DePinho RA
影响因子：
3.3
作者：
Komatsubara, Kimberly M.;Manson, Daniel K.;Carvajal, Richard D.
通讯作者：
Carvajal, Richard D.
影响因子：
4.4
作者：
Li, Li;Hu, Dan-Ning;Boissy, Raymond E.
通讯作者：
Boissy, Raymond E.
影响因子：
3.1
作者：
Chow, L;Berube, J;Bell, JB
通讯作者：
Bell, JB
影响因子：
11.2
作者：
Halder G;Camargo FD
通讯作者：
Camargo FD