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The expansion of ‘mutant’ cells that could lead to cancer is often restricted by their neighbours

last modified Jul 06, 2020 03:05 PM

Spatial competition shapes the dynamic mutational landscape of normal oesophageal epithelium

Some DNA mutations, particularly those affecting known ‘cancer genes’ such as TP53 and NOTCH1, confer a competitive advantage on cells that acquire them. This allows these mutant clones to expand more rapidly than normal cells and can lead to disease. By middle age, most cells in tissues such as the oesophagus and the skin are mutant clones. But despite this, the vast majority do not go on to form cNatureGenLogoancers. A previous study from the same groups has shown that clones competing against each other helps to prevent cancer formation, but until now the ‘rules of the game’ for clonal competition were unknown. To discover how mutant clones interact, the researchers combined genetic lineage tracing and ultradeep sequencing and modelling.

This recent paPhilJonesGraphper published in Nature Genetics from Phil Jones’ group and involving Ben Hall’s group shows how mutated clones in morphologically normal oesophageal epithelium compete with one another. The mutational landscape generated in mice resembles that seen in aging humans with several of the same genes under strong genetic selection.  By tracking cohorts of clones over a year following diethylnitrosamine (DEN) treatment in this mutationally diverse tissue, the authors see how strongly competitive mutations, such as Notch1 come to take over the tissue through a proliferative advantage. However, when clones of similar fitness collide, their proliferative behaviour reverts towards normal. This ‘neighbour constraint’ behaviour is consistent with findings in human skin and oesophagus.  Understanding the rules that constrain mutant clones in normal tissues is an important step in discovering interventions to reshape the mutational burden of clones in normal tissues to cut the chances of later developing cancer.

The study thus describes the ‘rules of the game’ of competition between oesophageal cells for the first time. By understanding these rules, the hope is that therapies can be developed to reduce the competitiveness of mutant clone cells that are more likely to become cancerous.