Selway-Clarke, Hugh;
(2025)
Computational approaches to study the effect of smoking on somatic evolution in the healthy human lung.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Recent single-cell genomic analysis of healthy human upper airway epithelial tissue has shown remarkable intra-tissue heterogeneity in the degree of effect smoking has on mutational burden, as well as an expansion of less-mutated basal cell subpop- ulations after smoking cessation. These two findings suggest potential mechanisms for somatic evolution in the healthy lung, which forms the backdrop for lung cancer formation. This may also explain epidemiological trends in the incidence of lung cancer subtypes, with lung squamous cell carcinoma falling in incidence in relation to lung adenocarcinoma as the fraction of the population who continue to smoke falls. Here, we use spatial agent-based computational modelling, building on a model of lung homeostasis previously verified by lineage tracing, to assess the ability of these hypotheses to reproduce observations. Applying machine learning methodology via a set of biologically motivated metrics to simulations of basal lung cell populations over the course of patients’ lifetimes, we find preliminary evidence for a slow cycling population of stem cells in the upper airway epithelium. The simulations suggest that this subpopulation, in combination with immune targeting of highly mutated cells being dampened during smoking, can best reproduce the unexpected dynamics seen in the data. This thesis traces a decades-long epidemiological trend to its tissue-level mechanistic cause in order to streamline future research into the early detection and prevention of lung cancer.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Computational approaches to study the effect of smoking on somatic evolution in the healthy human lung |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10208766 |
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