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Simulations reveal that different responses to cell crowding determine the expansion of p53 and Notch mutant clones in squamous epithelia.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Kostiou, Vasiliki 
Jones, Philip H 

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.

Description

Funder: MRC Cancer unit


Funder: Clare College

Keywords

cell competition, clonal evolution, epithelial dynamics, somatic mutation, spatial modelling, Animals, Carcinoma, Squamous Cell, Clone Cells, Epithelium, Mice, Mutation, Receptor, Notch1, Tumor Suppressor Protein p53

Journal Title

J R Soc Interface

Conference Name

Journal ISSN

1742-5689
1742-5662

Volume Title

Publisher

The Royal Society
Sponsorship
Cancer Research UK (C609/A17257)
Medical Research Council (MC_UU_12022/9)
Medical Research Council (MR/S000216/1)