Apr 1, 2020

Different responses to cell crowding determine the clonal fitness of p53 and Notch inhibiting mutations in squamous epithelia

BioRxiv : the Preprint Server for Biology
Lawrence H. UricchioBenjamin A Hall

Abstract

The growth and competition of cells in epithelial tissues plays an important role in both tissue homeostasis and the robustness of normal tissues to pre-cancer mutation. Whilst wild-type cells compete neutrally for dominance in the un-mutated tissue, naturally occurring mutations in individual cells may lend them a fitness advantage that can allow tissue colonisation. In mouse oesophageal epithelia, the growth of p53 mutants and a dominant negative mutant of the Notch downstream target Maml1 (DN_Maml1) have been shown to have different colonisation properties despite strong quantitative similarities in the growth of individual clones. Here we show that in order to recapitulate these behaviours whilst maintaining tissue turnover models need to take account of the response of cells to increased areal density in the tissue colonised by mutant cells. We demonstrate that p53 mutant clone growth approximates a logistic curve, but that without including limitations on mutation induced expansion the overall proliferation rate of the tissue drops due to space restrictions. In contrast, the ability of DN_Maml1 mutations to displace the wild-type population reflects a feedback that effects both mutant and wild-type cells equally. We go on...Continue Reading

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Mentioned in this Paper

Size
Empirical Study
Simulation
Alleles
Gene Mutant
Genetic Loci
EAF2 gene

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