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

Amanda R Moore1, Leili Ran2, Youxin Guan3

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, Cornell University, 1300 York Avenue, New York, NY 10065, USA.

Cell Reports
|March 1, 2018
PubMed

Insights

Uveal melanoma (UM) development involves GNAQ/GNA11 mutations and BAP1 loss. RasGRP3 is crucial for GNAQ/GNA11-driven Ras activation and tumorigenesis in UM, presenting a potential therapeutic target.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Uveal melanoma (UM) is driven by mutations in GNAQ, GNA11, CYSLTR2, or PLCB4, leading to PLCβ activation.
  • Aggressive UM subsets exhibit BAP1 loss.
  • Mouse models are crucial for understanding UM pathogenesis.

Purpose of the Study:

  • To investigate the role of GNA11 mutations and BAP1 loss in UM development.
  • To identify key molecular players in GNAQ/GNA11-driven melanomas.
  • To explore RasGRP3 as a potential therapeutic target in UM.

Main Methods:

  • Generated mice with melanocyte-specific GNA11Q209L expression, with and without Bap1 loss.
  • Analyzed tumor development in various organs.
  • Performed integrative transcriptome analysis of human and murine melanomas.

Main Results:

  • GNA11Q209L mice developed melanomas in cutaneous and non-cutaneous sites, mimicking human UM.
  • Bap1 loss accelerated tumor proliferation and increased melanoma size.
  • RasGRP3 was identified as specifically expressed and required for Ras activation and tumorigenesis in GNAQ/GNA11-driven melanomas.

Conclusions:

  • GNA11Q209L expression with Bap1 loss models aggressive UM.
  • RasGRP3 is a critical mediator of GNAQ/GNA11-driven tumorigenesis.
  • RasGRP3 represents a promising therapeutic target for UM.
Keywords:
BAP1BRAFGNA11GNAQRASGRP3genetically engineered mouse modelleptomeningeal melanocytomamelanomauveal melanoma

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