YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression

Abstract

Summary: 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. : Li et al. utilize an AAV-based ocular injection method to specifically manipulate Hippo/YAP and Ras signaling in mouse uveal melanocytes. They reveal the role of YAP/TAZ in uveal melanoma formation and suggest that the Hippo/YAP-Ras/MAPK interaction during tumor growth can be exploited to develop a therapeutic strategy for uveal melanoma. Keywords: uveal melanoma, Hippo/YAP, Ras/MAPK, tumor initiation, tumor progression, dual inhibition, mouse model, AAV ocular injection