Colom, B;
Herms, A;
Hall, MWJ;
Dentro, SC;
King, C;
Sood, RK;
Alcolea, MP;
... Jones, PH; + view all
(2021)
Mutant clones in normal epithelium outcompete and eliminate emerging tumours.
Nature
, 598
pp. 510-514.
10.1038/s41586-021-03965-7.
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Abstract
Human epithelial tissues accumulate cancer-driver mutations with age, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells 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. 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.
| Type: | Article |
|---|---|
| Title: | Mutant clones in normal epithelium outcompete and eliminate emerging tumours |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41586-021-03965-7 |
| Publisher version: | https://doi.org/10.1038/s41586-021-03965-7 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Cancer genomics, Cancer models |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10137063 |
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