1. Cancer Biology
  2. Chromosomes and Gene Expression
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Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma

  1. Floris Foijer  Is a corresponding author
  2. Lee A Albacker
  3. Bjorn Bakker
  4. Diana C Spierings
  5. Ying Yue
  6. Stephanie Z Xie
  7. Stephanie H Davis
  8. Annegret Lutum-Jehle
  9. Darin Takemoto
  10. Brian Hare
  11. Brinley Furey
  12. Roderick T Bronson
  13. Peter M Lansdorp
  14. Allan Bradley
  15. Peter K Sorger  Is a corresponding author
  1. University Medical Center Groningen, Netherlands
  2. Harvard Medical School, United States
  3. University Health Network, Canada
  4. Vertex Pharmaceuticals Incorporated, United States
  5. BC Cancer Agency, Canada
  6. Wellcome Trust Sanger Institute, United Kingdom
Research Article
  • Cited 28
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Cite this article as: eLife 2017;6:e20873 doi: 10.7554/eLife.20873

Abstract

Chromosome instability (CIN) is deleterious to normal cells because of the burden of aneuploidy. However, most human solid tumors have an abnormal karyotype implying that gain and loss of chromosomes by cancer cells confers a selective advantage. CIN can be induced in the mouse by inactivating the spindle assembly checkpoint. This is lethal in the germline but we show here that adult T cells and hepatocytes can survive conditional inactivation of the Mad2l1 SAC gene and resulting CIN. This causes rapid onset of acute lymphoblastic leukemia (T-ALL) and progressive development of hepatocellular carcinoma (HCC), both lethal diseases. The resulting DNA copy number variation and patterns of chromosome loss and gain are tumor-type specific, suggesting differential selective pressures on the two tumor cell types.

Data availability

The following data sets were generated
    1. Albacker
    (2015) Cytogenetic aberrations in Hepatocellular adenoma and carcinoma
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE63100).
    1. Albacker
    (2015) Hepatocellular adenoma/carcinoma from Mad2 deficient hepatocytes
    Publicly available at the NCBI Sequence Read Archive (accession no: SRA191233).
The following previously published data sets were used
    1. National Cancer Institute
    (2017) TGCA
    https://cancergenome.nih.gov.

Article and author information

Author details

  1. Floris Foijer

    European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands
    For correspondence
    f.foijer@umcg.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0989-3127
  2. Lee A Albacker

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Bjorn Bakker

    European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Diana C Spierings

    European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Ying Yue

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Stephanie Z Xie

    Princess Margaret and Toronto General Hospitals, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Stephanie H Davis

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0022-4210
  8. Annegret Lutum-Jehle

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Darin Takemoto

    Vertex Pharmaceuticals Incorporated, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Brian Hare

    Vertex Pharmaceuticals Incorporated, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Brinley Furey

    Vertex Pharmaceuticals Incorporated, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Roderick T Bronson

    Rodent Histopathology Core Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Peter M Lansdorp

    Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  14. Allan Bradley

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Peter K Sorger

    Department of Systems Biology, Harvard Medical School, Boston, United States
    For correspondence
    peter_sorger@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institute for Health Research (CA084179)

  • Lee A Albacker
  • Ying Yue
  • Stephanie H Davis
  • Peter K Sorger

National Institute for Health Research (CA139980)

  • Lee A Albacker
  • Ying Yue
  • Stephanie H Davis
  • Peter K Sorger

KWF Kankerbestrijding (2012-RUG-5549)

  • Floris Foijer
  • Bjorn Bakker

H2020 European Research Council (ERC advanced ROOTS)

  • Diana C Spierings
  • Peter M Lansdorp

European Molecular Biology Organization (Longterm fellowship)

  • Floris Foijer

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

Ethics

Animal experimentation: All animals were kept in pathogen-free housing under guidelines approved by the Center for Animal Resources and Comparative Medicine at Harvard Medical School or at the Wellcome Trust Sanger Institute. Animal protocols were approved by the Massachusetts Institute of Technology, Harvard Medical School Committees on Animal Care (IACUC numbers I04272 and IS00000178), UK Home Office, and UMCG animal facility (DEC 6369).

Reviewing Editor

  1. Angelika Amon, Howard Hughes Medical Institute, Massachusetts Institute of Technology, United States

Publication history

  1. Received: August 23, 2016
  2. Accepted: March 18, 2017
  3. Accepted Manuscript published: March 20, 2017 (version 1)
  4. Version of Record published: April 21, 2017 (version 2)

Copyright

© 2017, Foijer 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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Further reading

    1. Cancer Biology
    2. Cell Biology
    Lauren K Williams et al.
    Research Article Updated

    The abscission checkpoint regulates the ESCRT membrane fission machinery and thereby delays cytokinetic abscission to protect genomic integrity in response to residual mitotic errors. The checkpoint is maintained by Aurora B kinase, which phosphorylates multiple targets, including CHMP4C, a regulatory ESCRT-III subunit necessary for this checkpoint. We now report the discovery that cytoplasmic abscission checkpoint bodies (ACBs) containing phospho-Aurora B and tri-phospho-CHMP4C develop during an active checkpoint. ACBs are derived from mitotic interchromatin granules, transient mitotic structures whose components are housed in splicing-related nuclear speckles during interphase. ACB formation requires CHMP4C, and the ESCRT factor ALIX also contributes. ACB formation is conserved across cell types and under multiple circumstances that activate the checkpoint. Finally, ACBs retain a population of ALIX, and their presence correlates with delayed abscission and delayed recruitment of ALIX to the midbody where it would normally promote abscission. Thus, a cytoplasmic mechanism helps regulate midbody machinery to delay abscission.

    1. Cancer Biology
    Luca Tirinato et al.
    Research Article

    Although much progress has been made in cancer treatment, the molecular mechanisms underlying cancer radioresistance (RR) as well as the biological signatures of radioresistant cancer cells still need to be clarified. In this regard, we discovered that breast, bladder, lung, neuroglioma and prostate 6 Gy X-ray resistant cancer cells were characterized by an increase of Lipid Droplet (LD) number and that the cells containing highest LDs showed the highest clonogenic potential after irradiation. Moreover, we observed that LD content was tightly connected with the iron metabolism and in particular with the presence of the ferritin heavy chain (FTH1). In fact, breast and lung cancer cells silenced for the FTH1 gene showed a reduction in the LD numbers and, by consequence, became radiosensitive. FTH1 overexpression as well as iron-chelating treatment by Deferoxamine were able to restore the LD amount and RR. Overall, these results provide evidence of a novel mechanism behind RR in which LDs and FTH1 are tightly connected to each other, a synergistic effect which might be worth deeply investigating in order to make cancer cells more radiosensitive and improve the efficacy of radiation treatments.