1. Cancer Biology
  2. Stem Cells and Regenerative Medicine
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Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium

  1. Madeline Sandoval
  2. Zhe Ying
  3. Slobodan Beronja  Is a corresponding author
  1. Fred Hutchinson Cancer Research Center, United States
Research Article
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Cite this article as: eLife 2021;10:e54618 doi: 10.7554/eLife.54618

Abstract

Skin epithelium can accumulate a high burden of oncogenic mutations without morphological or functional consequences. To investigate the mechanism of oncogenic tolerance, we induced HrasG12V in single murine epidermal cells and followed them long-term. We observed that HrasG12V promotes an early and transient clonal expansion driven by increased progenitor renewal that is replaced with an increase in progenitor differentiation leading to reduced growth. We attribute this dynamic effect to emergence of two populations within oncogenic clones: renewing progenitors along the edge and differentiating ones within the central core. As clone expansion is accompanied by progressive enlargement of the core and diminishment of the edge compartment, the intra-clonal competition between the two populations results in stabilized oncogenic growth. To identify the molecular mechanism of HrasG12V-driven differentiation, we screened known Ras-effector in vivo, and identified Rassf5 as a novel regulator of progenitor fate choice that is necessary and sufficient for oncogene-specific differentiation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data file has been provided for Supplementary File 1.

Article and author information

Author details

  1. Madeline Sandoval

    Human Biology, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Zhe Ying

    Human Biology, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Slobodan Beronja

    Human Biology, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    beronja@fredhutch.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6769-9261

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR070780)

  • Slobodan Beronja

Cell and Molecular Biology Training Grant (Graduate Student Fellowship)

  • Madeline Sandoval

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 experimentation: Mice were housed and cared for in an AAALAC-accredited facility at Fred Hutchinson Cancer Research Center. All animal experiments were conducted under approved IACUC protocol number 50814 (approval date 12/01/2018-11/29/2021).

Reviewing Editor

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

Publication history

  1. Received: December 19, 2019
  2. Accepted: December 31, 2020
  3. Accepted Manuscript published: January 4, 2021 (version 1)
  4. Version of Record published: January 20, 2021 (version 2)

Copyright

© 2021, Sandoval 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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