Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

  1. Nataša Pavlović
  2. Carlemi Calitz
  3. Kess Thanapirom
  4. Guiseppe Mazza
  5. Krista Rombouts
  6. Pär Gerwins
  7. Femke Heindryckx  Is a corresponding author
  1. Uppsala University, Sweden
  2. University College London, United Kingdom

Abstract

Hepatocellular carcinoma (HCC) is a liver tumor that usually arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC-cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IREα in stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which then decreased proliferation and migration of tumor cells in different in vitro 2D and 3D co-cultures. In addition, we also observed cell-line specific direct effects of inhibiting IRE1α in tumor cells.

Data availability

Proteomics data has been deposited in Dryad with the following DOI: https://doi.org/10.5061/dryad.6wwpzgmv2

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Nataša Pavlović

    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  2. Carlemi Calitz

    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  3. Kess Thanapirom

    University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Guiseppe Mazza

    University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Krista Rombouts

    University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Pär Gerwins

    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  7. Femke Heindryckx

    Medical Cell Biology, Uppsala University, Uppsala, Sweden
    For correspondence
    femke.heindryckx@mcb.uu.se
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1987-7676

Funding

Cancerfonden (CAN 2017/518)

  • Femke Heindryckx

Svenska Sällskapet för Medicinsk Forskning (S17-0092)

  • Femke Heindryckx

OE och Edla Johanssons stiftelse

  • Femke Heindryckx

Olga Jonssons stiftelse

  • Femke Heindryckx

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations by FELASA. All of the animals were handled according to approved institutional animal care and Uppsala University approved protocols were used. The protocol was approved by the Committee on the Ethics of Animal Experiments of Uppsala (C95/14). All effort was made to minimise suffering and to decrease animal usage.

Reviewing Editor

  1. Lynne-Marie Postovit, University of Alberta, Canada

Publication history

  1. Received: February 9, 2020
  2. Accepted: October 26, 2020
  3. Accepted Manuscript published: October 26, 2020 (version 1)
  4. Version of Record published: November 12, 2020 (version 2)

Copyright

© 2020, Pavlović 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. Nataša Pavlović
  2. Carlemi Calitz
  3. Kess Thanapirom
  4. Guiseppe Mazza
  5. Krista Rombouts
  6. Pär Gerwins
  7. Femke Heindryckx
(2020)
Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma
eLife 9:e55865.
https://doi.org/10.7554/eLife.55865

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