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Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells

Author

Listed:
  • D. J. Huels

    (CRUK Beatson Institute)

  • L. Bruens

    (Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    The Netherlands Cancer Institute
    University Medical Center Utrecht)

  • M. C. Hodder

    (CRUK Beatson Institute)

  • P. Cammareri

    (CRUK Beatson Institute)

  • A. D. Campbell

    (CRUK Beatson Institute)

  • R. A. Ridgway

    (CRUK Beatson Institute)

  • D. M. Gay

    (CRUK Beatson Institute)

  • M. Solar-Abboud

    (CRUK Beatson Institute)

  • W. J. Faller

    (CRUK Beatson Institute)

  • C. Nixon

    (CRUK Beatson Institute)

  • L. B. Zeiger

    (CRUK Beatson Institute)

  • M. E. McLaughlin

    (Novartis Institutes for Biomedical Research)

  • E. Morrissey

    (John Radcliffe Hospital)

  • D. J. Winton

    (CRUK Cambridge Institute)

  • H. J. Snippert

    (University Medical Center Utrecht)

  • J. van Rheenen

    (Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    The Netherlands Cancer Institute)

  • O. J. Sansom

    (CRUK Beatson Institute
    University of Glasgow)

Abstract

Many epithelial stem cell populations follow a pattern of stochastic stem cell divisions called 'neutral drift'. It is hypothesised that neutral competition between stem cells protects against the acquisition of deleterious mutations. Here we use a Porcupine inhibitor to reduce Wnt secretion at a dose where intestinal homoeostasis is maintained despite a reduction of Lgr5+ stem cells. Functionally, there is a marked acceleration in monoclonal conversion, so that crypts become rapidly derived from a single stem cell. Stem cells located further from the base are lost and the pool of competing stem cells is reduced. We tested whether this loss of stem cell competition would modify tumorigenesis. Reduction of Wnt ligand secretion accelerates fixation of Apc-deficient cells within the crypt leading to accelerated tumorigenesis. Therefore, ligand-based Wnt signalling influences the number of stem cells, fixation speed of Apc mutations and the speed and likelihood of adenoma formation.

Suggested Citation

  • D. J. Huels & L. Bruens & M. C. Hodder & P. Cammareri & A. D. Campbell & R. A. Ridgway & D. M. Gay & M. Solar-Abboud & W. J. Faller & C. Nixon & L. B. Zeiger & M. E. McLaughlin & E. Morrissey & D. J. , 2018. "Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03426-2
    DOI: 10.1038/s41467-018-03426-2
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