YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression
Cotton, Jennifer L.
Zhu, Lihua Julie
Deng, April C.
Ip, Y. Tony
Johnson, Randy L.
UMass Chan AffiliationsDepartment of Pathology
Department of Ophthalmology and Visual Sciences
Program in Molecular Medicine
Department of Molecular, Cell and Cancer Biology
Document TypeJournal Article
KeywordsAAV ocular injection
Amino Acids, Peptides, and Proteins
Enzymes and Coenzymes
MetadataShow full item record
AbstractUveal 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.
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
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/41301
RightsCopyright 2019 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Except where otherwise noted, this item's license is described as Copyright 2019 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).