Owen, Kimberley A.;
(2025)
Harnessing synthetic biology to target oncogenic pathogens in colon cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Colorectal cancer is the 4th most common cancer in the UK. Patients with high levels of the bacteria Fusobacterium nucleatum (F. nucleatum) and Bacteroides fragilis (B. fragilis) within their tumours are associated with poorer survival outcomes. F. nucleatum promotes pro-inflammatory cytokines, tumour-immune cytokines, cancer stem cell-like states, genome instability/mutation, epithelial tight junction damage and supports chemotherapy component breakdown. Enterotoxigenic Bf (Ent. B. fragilis) strains produce a toxin, fragilysin, that forms biofilms, damages epithelial tight junctions, and induces inflammatory intestinal responses. We hypothesise that future therapies that remove pathogens such as F. nucleatum and Ent. B. fragilis from the tumour microenvironment could improve the success of chemotherapy and therefore patient outcomes. One approach is to remove these bacteria from the tumour environment by selectively killing them using an engineered live bacterial therapeutic product (eLBP). The eLBP would achieve this by using small, highly specific, antimicrobial peptides known as bacteriocins. Overall, this work had the following goals: 1) to identify bacteriocins that can target F. nucleatum/Ent. B. fragilis and 2) to build an eLBP that could deliver them. Bacteriocins that successfully kill F. nucleatum/B. fragilis were identified, and a number of delivery systems were explored, including secretion and lysis circuits. The bacteriocin, Aureocin A53 was successfully delivered, via a lysis circuit, but further work is required to express bacteriocin at high enough concentrations to kill the onco-pathogens. We investigated cancer patients’ attitudes towards this technology through a charity associated survey, which we found to be positive. This work highlights some of the challenges involved in building bacteriocin secreting eLBPs and can provide directions for building generic eLBPs to target the emerging pathobionts that interfere with chemotherapeutic treatment and drug-microbiome interactions more generally.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Harnessing synthetic biology to target oncogenic pathogens in colon cancer |
| Open access status: | An open access version is available from UCL Discovery |
| 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 > Eastman Dental Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Eastman Dental Institute > Microbial Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10209627 |
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