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Cited by 192Cancer Genomics and DiagnosticsCancer Cells and MetastasisEvolution and Genetic Dynamics

Mutant clones in normal epithelium outcompete and eliminate emerging tumours

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Colom, B., Herms, A., Hall, M. W. J., Dentro, S. C., King, C., Sood, R. K., Alcolea, M. P., Piedrafita, G. +8 more·2021·Nature
DOI 10.1038/s41586-021-03965-7PMC PMC7612642

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Abstract

Human epithelial tissues accumulate cancer-driver mutations with age 1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells 10-12. 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 neighbours 11-14. 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.

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  • In the esophagus, clonally expanding epithelial cells restrict tumorigenesis by outcompeting emerging cancer cells.

    “In the esophagus, clonally expanding epithelial cells restrict tumorigenesis by outcompeting emerging cancer cells (29, 30).”

    From Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion (2025) · cites this paper as [30]

    The Abstract and ‘Epithelial mutant clones displace tumors’ section report that expanding mutant clones in normal mouse esophageal epithelium eliminate early tumors through competition. The claim omits the mouse-model qualification and calls the emerging, pre-malignant tumor cells ‘cancer cells’; the Discussion says whether the mechanism occurs in humans is unknown. (LLM, conf=0.84)

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References 57 · Cited by 192

Research works printed but not linked: 42

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Authors
Colom, B., Herms, A., Hall, M. W. J., Dentro, S. C., King, C., Sood, R. K., Alcolea, M. P., Piedrafita, G., Fernandez-Antoran, D., Ong, S. H., Fowler, J. C., Mahbubani, K. T., Saeb-Parsy, K., Gerstung, M., Hall, B. A., & Jones, P. H.
Affiliations
  • Wellcome Sanger Institute (GB)
  • University of Cambridge (GB)
  • European Bioinformatics Institute (GB)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • NIHR Cambridge Biomedical Research Centre (GB)
  • University College London (GB)
Corresponding author
Jones, P. H.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-10-13
Volume
598
Issue
7881
Pages
510-514
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03965-7
PMC
PMC7612642
OpenAlex
W3207879702
Cited by
192
References
57
Citations by year
2026: 24 · 2025: 33 · 2024: 40 · 2023: 42 · 2022: 46 · 2021: 7
FWCI
13.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Wellcome Trust (296194, 098051)
  • European Bioinformatics Institute
  • Chan Zuckerberg Initiative
  • Cancer Research UK (27326, A27326, A17257, C/609/A17257, 17257, C609/A27326)
  • Royal Society (UF130039)
  • Russian Science Foundation
  • Medical Research Council (098051, MC_UU_00014/5, MR/S000216/1, MC_PC_17230, MR/S000216/2, MC_UU_12022/9)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Keywords
clonal competition, early tumorigenesis, esophageal cancer, mutant clones, cancer driver mutations, cell competition, clonal selection, tissue integrity
MeSH terms
Cell Competition, Animals, Cell Survival, Clone Cells, Disease Models, Animal, Epithelial Cells, Epithelium, Esophageal Neoplasms, Female, Male, Mutation, Time Factors, Cell Death, Cell Proliferation, Mice, Carcinogenesis

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