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• W769707696 abstract "Human cancers exhibit the common phenotype of elevated glycolytic metabolism, which causes acidification of the tissue microenvironment and may facilitate tumour invasion. In this thesis, we use mathematical models to address a series of open problems underlying the glycolytic tumour phenotype and its attendant acidity. We first explore tissue-scale consequences of metabolically-derived acid. Incorporating more biological detail into a canonical model of acidity at the tumour-host interface, we extend the range of tumour behaviours captured by the modelling framework. We then carry out an asymptotic travelling wave analysis to express invasive tumour properties in terms of fundamental parameters, and find that interstitial gaps between an advancing tumour and retreating healthy tissue, characteristic of aggressive invasion and comprising a controversial feature of the original model, are less significant under our generalised formulation. Subsequently, we evaluate a potential role of lactate---historically assumed to be a passive byproduct of glycolytic metabolism---in a perfusion-dependent metabolic symbiosis that was recently proposed as a beneficial tumour behaviour. Upon developing a minimal model of dual glucose-lactate consumption in vivo and employing a multidimensional sensitivity analysis, we find that symbiosis may not be straightforwardly beneficial for our model tumour. Moreover, new in vitro experiments, carried out by an experimental collaborator, place U87 glioblastoma tumours in a weakly symbiotic parameter regime despite their clinical malignancy. These results suggest that intratumoural metabolic cooperation is unlikely to be an important role for lactate. Finally, we examine the complex pH regulation system that governs expulsion of metabolically derived acid loads across tumour cell membranes. This system differs from the healthy system by expression of only a few key proteins, yet its dynamics are non-intuitive in the crowded and poorly perfused in vivo environment. We systematically develop a model of tumour pH regulation, beginning with a single-cell scenario and progressing to a spheroid, within a Bayesian framework that incorporates information from in vitro data contributed by a second experimental collaborator. We predict that a net effect of pH regulation is a straightforward transmembrane pH gradient, but also that existing treatments are unable to disrupt the system strongly enough to cause tumour cell death. Taken together, our models help to elucidate previously unresolved features of glycolytic tumour metabolism, and illustrate the utility of a combined mathematical, statistical, and experimental approach for testing biological hypotheses. Opportunities for further investigation are discussed." @default.
• W769707696 created "2016-06-24" @default.
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• W769707696 date "2014-01-01" @default.
• W769707696 modified "2023-09-27" @default.
• W769707696 title "Mathematical modelling of metabolism and acidity in cancer" @default.
• W769707696 hasPublicationYear "2014" @default.
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