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

Cell Rep. 2018 Feb 27;22(9):2455-2468. doi: 10.1016/j.celrep.2018.01.081.

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.

Keywords: BAP1; BRAF; GNA11; GNAQ; RASGRP3; genetically engineered mouse model; leptomeningeal melanocytoma; melanoma; uveal melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Lineage / drug effects
  • Cell Proliferation / drug effects
  • Central Nervous System Neoplasms / pathology
  • Disease Models, Animal
  • Female
  • GTP-Binding Protein alpha Subunits / metabolism*
  • Humans
  • Male
  • Melanocytes / drug effects
  • Melanocytes / metabolism*
  • Melanocytes / pathology
  • Melanoma / metabolism*
  • Melanoma / pathology*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm Invasiveness
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction* / drug effects
  • Skin Neoplasms / pathology
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin Thiolesterase / metabolism
  • Uveal Neoplasms / metabolism*
  • Uveal Neoplasms / pathology*
  • ras Guanine Nucleotide Exchange Factors / metabolism*

Substances

  • BAP1 protein, mouse
  • GNA11 protein, mouse
  • GTP-Binding Protein alpha Subunits
  • Protein Kinase Inhibitors
  • RasGRP3 protein, mouse
  • Tumor Suppressor Proteins
  • ras Guanine Nucleotide Exchange Factors
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Ubiquitin Thiolesterase

Supplementary concepts

  • Uveal melanoma