| First Author | Li H | Year | 2019 |
| Journal | Cell Rep | Volume | 29 |
| Issue | 10 | Pages | 3200-3211.e4 |
| PubMed ID | 31801083 | Mgi Jnum | J:296787 |
| Mgi Id | MGI:6468823 | Doi | 10.1016/j.celrep.2019.03.021 |
| Citation | Li H, et al. (2019) YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression. Cell Rep 29(10):3200-3211.e4 |
| abstractText | 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. |
