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Precancer: Mutant clones in normal epithelium outcompete and eliminate esophageal micro-tumors

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, View ORCID ProfileM. Gerstung, View ORCID ProfileB.A. Hall, View ORCID ProfileP.H. Jones
doi: https://doi.org/10.1101/2021.06.25.449880
B. Colom
1Wellcome Sanger Institute, Hinxton CB10 1SA, UK
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A. Herms
1Wellcome Sanger Institute, Hinxton CB10 1SA, UK
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M.W.J. Hall
1Wellcome Sanger Institute, Hinxton CB10 1SA, UK
2Department of Medical Physics and Biomedical Engineering, University College London, Gower Street, London WC1E 6BT, UK
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S.C. Dentro
1Wellcome Sanger Institute, Hinxton CB10 1SA, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge CB10 1SD, UK
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C. King
1Wellcome Sanger Institute, Hinxton CB10 1SA, UK
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R.K. Sood
1Wellcome Sanger Institute, Hinxton CB10 1SA, UK
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M.P. Alcolea
4Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AW
5Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK
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G. Piedrafita
1Wellcome Sanger Institute, Hinxton CB10 1SA, UK
6Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain
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D. Fernandez-Antoran
1Wellcome Sanger Institute, Hinxton CB10 1SA, UK
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S.H. Ong
1Wellcome Sanger Institute, Hinxton CB10 1SA, UK
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J.C. Fowler
1Wellcome Sanger Institute, Hinxton CB10 1SA, UK
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K.T. Mahbubani
7Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, Cambridge CB2 0QQ
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K. Saeb-Parsy
7Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, Cambridge CB2 0QQ
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M. Gerstung
3European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge CB10 1SD, UK
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  • ORCID record for M. Gerstung
B.A. Hall
2Department of Medical Physics and Biomedical Engineering, University College London, Gower Street, London WC1E 6BT, UK
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P.H. Jones
1Wellcome Sanger Institute, Hinxton CB10 1SA, UK
2Department of Medical Physics and Biomedical Engineering, University College London, Gower Street, London WC1E 6BT, UK
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  • For correspondence: pj3@sanger.ac.uk
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Summary

Human epithelial tissues accumulate cancer-driver mutations with age1–7, yet tumor formation remains rare. The positive selection of these mutations argues they alter the behavior and fitness of proliferating cells8–10. Hence, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less-competitive neighbors9–12. However, little is known about how such dynamic competition in normal epithelia impacts early tumorigenesis. Here we show that the majority of newly formed esophageal tumors are eliminated through competition with mutant clones in the surrounding normal epithelium. We followed the fate of microscopic tumors in a mouse model of esophageal carcinogenesis. Most neoplasms are rapidly lost despite no indication of tumor cell death, decreased proliferation, or an anti-tumor immune response. Deep-sequencing of 10-day and 1-year-old tumors shows evidence of genetic selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased tumor removal, while pharmacologically inhibiting clonal competition reduced tumor loss. The results are consistent with a model where survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the adjacent normal tissue. We have identified an unexpected anti-tumorigenic role for mutant clones in normal epithelium by purging early neoplasms through cell competition, thereby preserving tissue integrity.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 25, 2021.
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Precancer: Mutant clones in normal epithelium outcompete and eliminate esophageal micro-tumors
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. Gerstung, B.A. Hall, P.H. Jones
bioRxiv 2021.06.25.449880; doi: https://doi.org/10.1101/2021.06.25.449880
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Precancer: Mutant clones in normal epithelium outcompete and eliminate esophageal micro-tumors
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. Gerstung, B.A. Hall, P.H. Jones
bioRxiv 2021.06.25.449880; doi: https://doi.org/10.1101/2021.06.25.449880

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