1. GNA11 Q209L Mouse Model Reveals RasGRP3 as an Essential Signaling Node in Uveal Melanoma.
- Author
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Moore AR, Ran L, Guan Y, Sher JJ, Hitchman TD, Zhang JQ, Hwang C, Walzak EG, Shoushtari AN, Monette S, Murali R, Wiesner T, Griewank KG, Chi P, and Chen Y
- Subjects
- Animals, Cell Line, Tumor, Cell Lineage drug effects, Cell Proliferation drug effects, Central Nervous System Neoplasms pathology, Disease Models, Animal, Female, Humans, Male, Melanocytes drug effects, Melanocytes pathology, Mitogen-Activated Protein Kinase Kinases metabolism, Mitogen-Activated Protein Kinases metabolism, Neoplasm Invasiveness, Protein Kinase Inhibitors pharmacology, Skin Neoplasms pathology, Tumor Suppressor Proteins metabolism, Ubiquitin Thiolesterase metabolism, GTP-Binding Protein alpha Subunits metabolism, Melanocytes metabolism, Melanoma metabolism, Melanoma pathology, Signal Transduction drug effects, Uveal Neoplasms metabolism, Uveal Neoplasms pathology, ras Guanine Nucleotide Exchange Factors metabolism
- Abstract
Uveal melanoma (UM) is characterized by mutually exclusive activating mutations in GNAQ, GNA11, CYSLTR2, and PLCB4, four genes in a linear pathway to activation of PLCβ in almost all tumors and loss of BAP1 in the aggressive subset. We generated mice with melanocyte-specific expression of GNA11
Q209L with and without homozygous Bap1 loss. The GNA11Q209L mice recapitulated human Gq-associated melanomas, and they developed pigmented neoplastic lesions from melanocytes of the skin and non-cutaneous organs, including the eye and leptomeninges, as well as at atypical sites, including the lymph nodes and lungs. The addition of Bap1 loss increased tumor proliferation and cutaneous melanoma size. Integrative transcriptome analysis of human and murine melanomas identified RasGRP3 to be specifically expressed in GNAQ/GNA11-driven melanomas. In human UM cell lines and murine models, RasGRP3 is specifically required for GNAQ/GNA11-driven Ras activation and tumorigenesis. This implicates RasGRP3 as a critical node and a potential target in UM., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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