Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma

  1. Oscar Urtatiz
  2. Amanda Haage
  3. Guy Tanentzapf
  4. Catherine D Van Raamsdonk  Is a corresponding author
  1. University of British Columbia, Canada

Abstract

Different melanoma subtypes exhibit specific and non-overlapping sets of oncogene and tumor suppressor mutations, despite a common cell of origin in melanocytes. For example, activation of the Gαq/11 signaling pathway is a characteristic initiating event in primary melanomas that arise in the dermis, uveal tract or central nervous system. It is rare in melanomas arising in the epidermis. The mechanism for this specificity is unknown. Here, we present evidence that in the mouse, crosstalk with the epidermal microenvironment actively impairs the survival of melanocytes expressing the GNAQQ209L oncogene. We found that GNAQQ209L, in combination with signaling from the interfollicular epidermis (IFE), stimulates dendrite extension, leads to actin cytoskeleton disorganization, inhibits proliferation and promotes apoptosis in melanocytes. The effect was reversible and paracrine. In contrast, the epidermal environment increased the survival of wildtype and BrafV600E expressing melanocytes. Hence, our studies reveal the flip side of Gaq/11 signaling, which was hitherto unsuspected. In the future, the identification of the epidermal signals that restrain the GNAQQ209L oncogene could suggest novel therapies for GNAQ and GNA11 mutant melanomas.

Data availability

Sequencing data has been deposited at the Sequencing Read Archive (SRA) of the NCBI under BioProjectID PRJNA736153.The custom MATLAB scripts have been deposited to GitHub at https://github.com/Tanentzapf-Lab/ActinOrganization_CellMorphology_Haage.All other data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Oscar Urtatiz

    Department of Medical Genetics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Amanda Haage

    Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6305-440X
  3. Guy Tanentzapf

    Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2443-233X
  4. Catherine D Van Raamsdonk

    Department of Medical Genetics, University of British Columbia, Vancouver, Canada
    For correspondence
    cvr@mail.ubc.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4309-3513

Funding

Canadian Institutes of Health Research (MOP-79511)

  • Catherine D Van Raamsdonk

Canadian Institutes of Health Research (PJT-168868)

  • Guy Tanentzapf

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal research was conducted under the approval of the University of British Columbia Animal Care Committee (Protocols A18-0080 and A19-0148, C.D.V.R.).

Reviewing Editor

  1. William C Hahn, Dana-Farber Cancer Institute, United States

Publication history

  1. Received: June 30, 2021
  2. Preprint posted: July 26, 2021 (view preprint)
  3. Accepted: December 21, 2021
  4. Accepted Manuscript published: December 23, 2021 (version 1)
  5. Version of Record published: January 10, 2022 (version 2)

Copyright

© 2021, Urtatiz et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Oscar Urtatiz
  2. Amanda Haage
  3. Guy Tanentzapf
  4. Catherine D Van Raamsdonk
(2021)
Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma
eLife 10:e71825.
https://doi.org/10.7554/eLife.71825

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