Clonal Competition in The Normal Oesophageal EpitheliumDuring Early Carcinogenesis

Human epithelial tissues accumulate cancer-driver mutationswith age, yet tumour formation remains rare. The positive selectionof these mutations argues they alter the behaviour andfitness of proliferating cells. Hence, normal adult tissues becomea patchwork of mutant clones competing for space andsurvival, with the fittes t clones expanding by eliminating theirless-competitive neighbours. However, little is known abouthow such dynamic competition in normal epithelia influencesearly tumorigenesis. To answer this ques tion, we have developedan in vivo mouse model that recapitulates the mutationallandscape of the normal human oesophageal epithelium. Wehave used transgenic mouse models, quantitative lineage tracing,ultra-deep DNA sequencing, whole-tissue confocal imagingand mathematical modelling to resolve the dynamics ofmutant clones in this tissue, and their role in the developmentof emerging tumours. Our results show that mutant clone dynamicsin the normal oesophageal epithelium are defined bythe relative fitness of clones competing for survival within thetissue confined space. In this environment, clones carrying particularmutations prevent early tumorigenesis by keeping incheck more malignant clones, and by directly outcompetingand eliminating emerging micro-tumours. Importantly, manipulatingthe normal epithelium mutational landscape influencesearly tumour formation, an approach that may lead to thedevelopment of novel preventive s trategies agains t cancer. Weconclude that mutant clones in normal epithelium have an unexpectedanti-tumorigenic role in purging early tumors throughcell competition, thereby preserving tissue integrity.