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Mutant clones in normal epithelium outcompete and eliminate emerging tumours

Author

Listed:
  • B. Colom

    (Wellcome Sanger Institute)

  • A. Herms

    (Wellcome Sanger Institute)

  • M. W. J. Hall

    (Wellcome Sanger Institute
    University of Cambridge, Hutchison–MRC Research Centre)

  • S. C. Dentro

    (Wellcome Sanger Institute
    European Bioinformatics Institute)

  • C. King

    (Wellcome Sanger Institute)

  • R. K. Sood

    (Wellcome Sanger Institute)

  • M. P. Alcolea

    (University of Cambridge
    University of Cambridge, Hutchison–MRC Research Centre)

  • G. Piedrafita

    (Wellcome Sanger Institute
    Spanish National Cancer Research Centre (CNIO))

  • D. Fernandez-Antoran

    (Wellcome Sanger Institute
    University of Cambridge)

  • S. H. Ong

    (Wellcome Sanger Institute)

  • J. C. Fowler

    (Wellcome Sanger Institute)

  • K. T. Mahbubani

    (Department of Surgery and Cambridge NIHR Biomedical Research Centre)

  • K. Saeb-Parsy

    (Department of Surgery and Cambridge NIHR Biomedical Research Centre)

  • M. Gerstung

    (European Bioinformatics Institute
    Genome Biology Unit)

  • B. A. Hall

    (University College London)

  • P. H. Jones

    (Wellcome Sanger Institute
    University of Cambridge, Hutchison–MRC Research Centre)

Abstract

Human epithelial tissues accumulate cancer-driver mutations with age1–9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10–12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11–14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.

Suggested Citation

  • B. Colom & A. Herms & M. W. J. Hall & S. C. Dentro & C. King & R. K. Sood & M. P. Alcolea & G. Piedrafita & D. Fernandez-Antoran & S. H. Ong & J. C. Fowler & K. T. Mahbubani & K. Saeb-Parsy & M. Gerst, 2021. "Mutant clones in normal epithelium outcompete and eliminate emerging tumours," Nature, Nature, vol. 598(7881), pages 510-514, October.
  • Handle: RePEc:nat:nature:v:598:y:2021:i:7881:d:10.1038_s41586-021-03965-7
    DOI: 10.1038/s41586-021-03965-7
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    Cited by:

    1. Nanase Igarashi & Kenichi Miyata & Tze Mun Loo & Masatomo Chiba & Aki Hanyu & Mika Nishio & Hiroko Kawasaki & Hao Zheng & Shinya Toyokuni & Shunsuke Kon & Keiji Moriyama & Yasuyuki Fujita & Akiko Taka, 2022. "Hepatocyte growth factor derived from senescent cells attenuates cell competition-induced apical elimination of oncogenic cells," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Szu-Hsien Sam Wu & Somi Kim & Heetak Lee & Ji-Hyun Lee & So-Yeon Park & Réka Bakonyi & Isaree Teriyapirom & Natalia Hallay & Sandra Pilat-Carotta & Hans-Christian Theussl & Jihoon Kim & Joo-Hyeon Lee , 2024. "Red2Flpe-SCON: a versatile, multicolor strategy for generating mosaic conditional knockout mice," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Kasumi Murai & Stefan Dentro & Swee Hoe Ong & Roshan Sood & David Fernandez-Antoran & Albert Herms & Vasiliki Kostiou & Irina Abnizova & Benjamin A. Hall & Moritz Gerstung & Philip H. Jones, 2022. "p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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