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January 28, 2025
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Mutant clones in normal epithelium outcompete and eliminate emerging tumours.

Publicated to:Nature. 598 (7881): 510-514 - 2021-10-01 598(7881), DOI: 10.1038/s41586-021-03965-7

Authors: Colom B; Herms A; Hall MWJ; Dentro SC; King C; Sood RK; Alcolea MP; Piedrafita G; Fernandez-Antoran D; Ong SH; Fowler JC; Mahbubani KT; Saeb-Parsy K; Gerstung M; Hall BA; Jones PH

Affiliations

Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom. - Author
Department of Surgery and Cambridge NIHR Biomedical Research Centre, Cambridge, UK. - Author
European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge, UK. - Author
Wellcome Sanger Institute, Hinxton, UK. - Author
Wellcome Sanger Institute, Hinxton, UK. pj3@sanger.ac.uk. - Author
Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK. - Author
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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.

Keywords

AnimalsCarcinogenesisCell competitionCell deathCell proliferationCell survivalClone cellsDisease models, animalEpithelial cellsEpitheliumEsophageal neoplasmsFemaleMaleMiceMutationTime factors

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Nature due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2021, it was in position 1/74, thus managing to position itself as a Q1 (Primer Cuartil), in the category Multidisciplinary Sciences. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 39.77, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Sep 2025)

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-09-04:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 314.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 316 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 287.4.
  • The number of mentions on the social network X (formerly Twitter): 693 (Altmetric).
  • The number of mentions in news outlets: 7 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United Kingdom.