Department of Molecular, Cell and Cancer Biology; Program in Molecular Medicine; Department of Ophthalmology and Visual Sciences; Department of Pathology
Amino Acids, Peptides, and Proteins | Cancer Biology | Enzymes and Coenzymes | Eye Diseases | Molecular Biology | Neoplasms | Ophthalmology | Pathology
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.
AAV ocular injection, Hippo/YAP, Ras/MAPK, dual inhibition, mouse model, tumor initiation, tumor progression, uveal melanoma
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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/).
DOI of Published Version
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
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. (2019). YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression. Open Access Articles. https://doi.org/10.1016/j.celrep.2019.03.021. Retrieved from https://escholarship.umassmed.edu/oapubs/4087
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
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