Mutant clones in normal epithelium outcompete and eliminate emerging tumours.
Nature
; 598(7881): 510-514, 2021 10.
Article
in En
| MEDLINE
| ID: mdl-34646013
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Esophageal Neoplasms
/
Clone Cells
/
Cell Proliferation
/
Epithelial Cells
/
Cell Competition
/
Mutation
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Nature
Year:
2021
Document type:
Article
Affiliation country:
United kingdom