UMMS Affiliation

Department of Molecular, Cell and Cancer Biology; Program in Molecular Medicine; Department of Ophthalmology and Visual Sciences; Department of Pathology

Publication Date

2019-12-03

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cancer Biology | Enzymes and Coenzymes | Eye Diseases | Molecular Biology | Neoplasms | Ophthalmology | Pathology

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.

Keywords

AAV ocular injection, Hippo/YAP, Ras/MAPK, dual inhibition, mouse model, tumor initiation, tumor progression, uveal melanoma

Rights and Permissions

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

10.1016/j.celrep.2019.03.021

Source

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

Journal/Book/Conference Title

Cell reports

Related Resources

Link to Article in PubMed

PubMed ID

31801083

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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