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GNA11 Q209L Mouse Model Reveals RasGRP3 as an Essential Signaling Node in Uveal Melanoma.

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 GNA11Q209L 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.

journal_name

Cell Rep

journal_title

Cell reports

authors

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,Chen Y

doi

10.1016/j.celrep.2018.01.081

subject

Has Abstract

pub_date

2018-02-27 00:00:00

pages

2455-2468

issue

9

issn

2211-1247

pii

S2211-1247(18)30145-1

journal_volume

22

pub_type

杂志文章

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