Mutant p53 in tumour cell interactions
File(s)
Author(s)
Pilley, Steven
Type
Thesis
Abstract
TP53 is the most frequently mutated gene in human cancer. Not only do tumour-associated mutant p53 proteins lose wild-type p53 tumour suppressor activity, but they can also inhibit wild-type p53 activity through dominant negative effects and demonstrate tumour-promoting gains of function. Some mutant p53 proteins also retain certain wild-type functions, which can support oncogenesis. Mutant p53 proteins are not inherently stable and as a result, show heterogenous expression patterns in tumours. However, interactions between tumour cells with and without mutant p53 are poorly understood. In this study, I found that some cancer cell lines expressing mutant p53 outcompete isogenic cells expressing no p53. The ability to outcompete cells without p53 is a wild-type p53 activity, retained by a common tumour-associated mutant, R248W, but not by another, R175H. Secretion of ligands, including WNT16, contributes to this process. p53-dependent tumour cell competition may be a mechanism for selecting cells with stable mutant p53 in tumours. In vitro, this competition occurs both in 2d monolayers and 3d spheroid culture. When cultured in 3d, some cell lines accumulate and excrete large amounts of proline due to changes in translation. Other cell types within the tumour microenvironment may take up proline excreted by tumour cells. These findings illustrate the complexity of interactions within tumours. Tumour cells with or without p53 may affect each other’s growth, while cell extrinsic factors such as cell detachment may affect interactions between tumour cells and other cell types.
Version
Open Access
Date Issued
2022-09-17
Date Awarded
01/06/2023
License URL
Advisor
Vousden, Karen
Rodriguez, Tristan
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)