1. Cancer Biology
  2. Genetics and Genomics
Download icon

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
Research Article
  • Cited 0
  • Views 387
  • Annotations
Cite this article as: eLife 2021;10:e71825 doi: 10.7554/eLife.71825

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.

Metrics

  • 387
    Page views
  • 91
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Genetics and Genomics
    Hirokazu Kimura et al.
    Research Article

    Pathogenic germline CDKN2A variants are associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). CDKN2A variants of uncertain significance (VUSs) are reported in up to 4.3% of patients with PDAC and result in significant uncertainty for patients and their family members as an unknown fraction are functionally deleterious, and therefore, likely pathogenic. Functional characterization of CDKN2A VUSs is needed to reclassify variants and inform clinical management. 29 germline CDKN2A VUSs previously reported in patients with PDAC or in ClinVar were evaluated using a validated in vitro cell proliferation assay. 12 of the 29 CDKN2A VUSs were functionally deleterious (11 VUSs) or potentially functionally deleterious (1 VUS) and were reclassified as likely pathogenic variants. Thus, over 40% of CDKN2A VUSs identified in patients with PDAC are functionally deleterious and likely pathogenic. When incorporating VUSs found to be functionally deleterious, and reclassified as likely pathogenic, the prevalence of pathogenic/likely pathogenic CDKN2A in patients with PDAC reported in the published literature is increased to up to 4.1% of patients, depending on family history. Therefore, CDKN2A VUSs may play a significant, unappreciated role in risk of pancreatic cancer. These findings have significant implications for the counselling and care of patients and their relatives.

    1. Cancer Biology
    2. Computational and Systems Biology
    Alexander P Browning et al.
    Research Article Updated

    Tumour spheroids are common in vitro experimental models of avascular tumour growth. Compared with traditional two-dimensional culture, tumour spheroids more closely mimic the avascular tumour microenvironment where spatial differences in nutrient availability strongly influence growth. We show that spheroids initiated using significantly different numbers of cells grow to similar limiting sizes, suggesting that avascular tumours have a limiting structure; in agreement with untested predictions of classical mathematical models of tumour spheroids. We develop a novel mathematical and statistical framework to study the structure of tumour spheroids seeded from cells transduced with fluorescent cell cycle indicators, enabling us to discriminate between arrested and cycling cells and identify an arrested region. Our analysis shows that transient spheroid structure is independent of initial spheroid size, and the limiting structure can be independent of seeding density. Standard experimental protocols compare spheroid size as a function of time; however, our analysis suggests that comparing spheroid structure as a function of overall size produces results that are relatively insensitive to variability in spheroid size. Our experimental observations are made using two melanoma cell lines, but our modelling framework applies across a wide range of spheroid culture conditions and cell lines.