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Title: Cell fate mechanisms in colorectal cancer
Author: Kay, Sophie Kate
ISNI:       0000 0004 4692 1665
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2014
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Colorectal cancer (CRC) arises in part from the dysregulation of cellular proliferation, associated with the canonical Wnt pathway, and differentiation, effected by the Notch signalling network. In this thesis, we develop a mathematical model of ordinary differential equations (ODEs) for the coupled interaction of the Notch and Wnt pathways in cells of the human intestinal epithelium. Our central aim is to understand the role of such crosstalk in the genesis and treatment of CRC. An embedding of this model in cells of a simulated colonic tissue enables computational exploration of the cell fate response to spatially inhomogeneous growth cues in the healthy intestinal epithelium. We also examine an alternative, rule-based model from the literature, which employs a simple binary approach to pathway activity, in which the Notch and Wnt pathways are constitutively on or off. Comparison of the two models demonstrates the substantial advantages of the equation-based paradigm, through its delivery of stable and robust cell fate patterning, and its versatility for exploring the multiscale consequences of a variety of subcellular phenomena. Extension of the ODE-based model to include mutant cells facilitates the study of Notch-mediated therapeutic approaches to CRC. We find a marked synergy between the application of γ-secretase inhibitors and Hath1 stabilisers in the treatment of early-stage intestinal polyps. This combined treatment is an efficient means of inducing mitotic arrest in the cell population of the intestinal epithelium through enforced conversion to a secretory phenotype and is highlighted as a viable route for further theoretical, experimental and clinical study.
Supervisor: Gavaghan, David; Byrne, Helen; Osborne, James Sponsor: Engineering & Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Computational biochemistry ; Biology ; Physiology and anatomy ; Mathematics ; Biology and other natural sciences (mathematics) ; Computer science (mathematics) ; Mathematical biology ; Ordinary differential equations ; Gastroenterology ; computational biology ; gut ; intestine ; Wnt ; Notch ; cancer modelling ; colorectal cancer