YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression
Li, Huapeng ; Li, Qi ; Dang, Kyvan ; Ma, Shan ; Cotton, Jennifer L. ; Yang, Sun ; Zhu, Lihua Julie ; Deng, April ; Ip, Y. Tony ; Johnson, Randy L. ... show 3 more
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Abstract
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 (GalphaQ/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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Cell Rep. 2019 Dec 3;29(10):3200-3211.e4. doi: 10.1016/j.celrep.2019.03.021. Link to article on publisher's site