Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma

Abstract

Quantitative differences in signal transduction are to date an understudied feature of tumour heterogeneity. The MAPK Erk pathway, which is activated in a large proportion of human tumours, is a prototypic example of distinct cell fates being driven by signal intensity. We have used primary hepatocyte precursors transformed with different dosages of an oncogenic form of Ras to model subclonal variations in MAPK signalling. Orthotopic allografts of Ras-transformed cells in immunocompromised mice gave rise to fast-growing aggressive tumours, both at the primary location and in the peritoneal cavity. Fluorescent labelling of cells expressing different oncogene levels, and consequently varying levels of MAPK Erk activation, highlighted the selection processes operating at the two sites of tumour growth. Indeed, significantly higher Ras expression was observed in primary as compared to secondary, metastatic sites, despite the apparent evolutionary trade-off of increased apoptotic death in the liver that correlated with high Ras dosage. Analysis of the immune tumour microenvironment at the two locations suggests that fast peritoneal tumour growth in the immunocompromised setting is abrogated in immunocompetent animals due to efficient antigen presentation by peritoneal dendritic cells. Furthermore, our data indicate that, in contrast to the metastatic-like outgrowth, strong MAPK signalling is required in the primary liver tumours to resist elimination by NK cells. Overall, this study describes a quantitative aspect of tumour heterogeneity and points to a potential vulnerability of a subtype of hepatocellular carcinoma as a function of MAPK Erk signalling intensity.

Data availability

The RNA-sequencing data have been deposited in the Gene Expression Omnibus (GEO, NCBI) repository, and are accessible through GEO Series accession number GSE180580. Raw data from figures 1 to 5 were deposited on Mendeley data at doi: 10.17632/73nbvs8925.1.

The following data sets were generated

Article and author information

Author details

  1. Anthony Lozano

    Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Francois-Régis Souche

    Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Carine Chavey

    Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Valérie Dardalhon

    Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Christel Ramirez

    Division of Tumor Biology and Immunology, Oncode Institute, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  6. Serena Vegna

    Division of Tumor Biology and Immunology, Oncode Institute, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Guillaume Desandre

    Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Anaïs Riviere

    Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Amal Zine El Aabidine

    Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Philippe Fort

    Centre de Recherche en Biologie Cellulaire de Montpellier, French National Centre for Scientific Research, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5997-8722
  11. Leila Akkari

    Division of Tumor Biology and Immunology, Oncode Institute, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  12. Urszula Hibner

    Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
    For correspondence
    ula.hibner@igmm.cnrs.fr
    Competing interests
    The authors declare that no competing interests exist.
  13. Damien Grégoire

    Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
    For correspondence
    damien.gregoire@igmm.cnrs.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1105-8115

Funding

SIRIC Montpellier Cancer (Grant INCa_Inserm_DGOS_12553)

  • Urszula Hibner

Grant HTE-ITMO Cancer (HTE201610)

  • Urszula Hibner

Association Francaise pour l'Etude du Foie

  • Damien Grégoire

Dutch Cancer Society (KWF 12049/2018-2)

  • Leila Akkari

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

Reviewing Editor

  1. Roger J Davis, University of Massachusetts Medical School, United States

Ethics

Animal experimentation: All reported animal procedures were carried out in accordance with the rules of the FrenchInstitutional Animal Care and Use Committee and European Community Council(2010/63/EU). Animal studies were approved by institutional ethical committee (Comitéd'éthique en expérimentation animale Languedoc-Roussillon (#36)) and by the Ministère del'Enseignement Supérieur, de la Recherche et de l'Innovation (APAFIS#11196-2018090515538313v2).

Version history

  1. Preprint posted: August 13, 2021 (view preprint)
  2. Received: December 13, 2021
  3. Accepted: January 18, 2023
  4. Accepted Manuscript published: January 19, 2023 (version 1)
  5. Version of Record published: February 1, 2023 (version 2)

Copyright

© 2023, Lozano 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. Anthony Lozano
  2. Francois-Régis Souche
  3. Carine Chavey
  4. Valérie Dardalhon
  5. Christel Ramirez
  6. Serena Vegna
  7. Guillaume Desandre
  8. Anaïs Riviere
  9. Amal Zine El Aabidine
  10. Philippe Fort
  11. Leila Akkari
  12. Urszula Hibner
  13. Damien Grégoire
(2023)
Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma
eLife 12:e76294.
https://doi.org/10.7554/eLife.76294

Share this article

https://doi.org/10.7554/eLife.76294

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