Kostiou, V; Hall, MWJ; Jones, PH; Hall, BA; (2021) Simulations reveal that different responses to cell crowding determine the expansion of p53 and Notch mutant clones in squamous epithelia. Journal of the Royal Society Interface , 18 (183) , Article 20210607. 10.1098/rsif.2021.0607.

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Abstract

During ageing, normal epithelial tissues progressively accumulate clones carrying mutations that increase mutant cell fitness above that of wild-type cells. Such mutants spread widely through the tissues, yet despite this cellular homeostasis and functional integrity of the epithelia are maintained. Two of the genes most commonly mutated in human skin and oesophagus are p53 and Notch1, both of which are also recurrently mutated in cancers of these tissues. From observations taken in human and mouse epithelia, we find that clones carrying p53 and Notch pathway mutations have different clone dynamics which can be explained by their different responses to local cell crowding. p53 mutant clone growth in mouse epidermis approximates a logistic curve, but feedbacks responding to local crowding are required to maintain tissue homeostasis. We go on to show that the observed ability of Notch pathway mutant cells to displace the wild-type population in the mouse oesophageal epithelium reflects a local density feedback that affects both mutant and wild-type cells equally. We then show how these distinct feedbacks are consistent with the distribution of mutations observed in human datasets and are suggestive of a putative mechanism to constrain these cancer-associated mutants.

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