BC-DTP_2027_09
Investigating a Novel Mechanism Regulating Cell Junctions in Colitis Using Primary Tissues and Patient-Derived Organoids
Primary Supervisor
Prof Angus Cameron
Institute/ School: Barts Cancer Institute
Secondary Supervisor
Prof James Lindsay
Institute/ School: Blizard Institute
Project Video
Lay Summary
Inflammatory Bowel Diseases (IBD), including Ulcerative Colitis and Crohn’s disease cause significant suffering and reduced quality of life for patients, and represent a large healthcare burden to the Barts Health NHS trust. The Royal London Hospital alone manages approximately 3,500 cases, and both the incidence and severity of disease disproportionately affect South Asian populations in East London. The underlying causes of IBD, and reasons for differences between patient populations, remain poorly defined
We recently identified a novel mechanism regulating the stability of junctions between the cells which line the bowel. When cell-junctions become weakened, toxins and bacteria can leak through the bowel wall resulting in inflammation and injury. Using data from human IBD samples, we have shown that loss of cell junctions through our novel mechanism is likely to be an underlying cause of IBD. In this project we will use samples from IBD patients to grow mini guts (organoids) in the laboratory. These organoids will be used to explore how our novel mechanism regulates junctions in different patients. Models will allow us to screen for novel approaches to strengthen cell-junctions as potential new IBD therapies. Tissue samples and data from diverse populations served by the Barts Health NHS trust will also be used to examine cell-junction regulation between different ethnic groups.
Project Goal: To define the importance of cell junction regulation in the development of IBD and identify novel ways to reverse junction breakdown to treat disease.
Aim 1: We will use human tissues and organoids to explore PKN2 regulation of junctions in patient samples.
Aim 2: Using organoid and cell models, we will identify therapeutic approaches to stabilise damaged cell junctions.
Aim 3: We will explore heterogeneity in PKN2 regulation of cell junctions across distinct patient populations, including different disease-types, ethnicity and age.
References
- Henry JC, Campbell A, Huddar P, Sewell J, Menezes S, Passman A, Smith K, McGauran S, Quétier I, Meng-Lay Lin M-L, Jansen M, McDonald N, Graham TA, McDonald S and Cameron AJM. PKN2 regulates cell-junctions to limit colitis. bioRxiv 2025.12.15.694339; Under Revision: Nature Communications. bioRxiv
doi: 10.64898/2025.12.15.694339. - Murray ER, Menezes S, Henry JC, Williams JL, Alba-Castellón L, Baskaran P, Quétier I, Desai A, Marshall JJT, Rosewell I, Tatari M, Rajeeve V, Khan F, Wang J, Kotantaki P, Tyler EJ, Singh N, Reader CS, Carter EP, Hodivala-Dilke K, Grose RP, Kocher HM, Gavara N, Pearce O, Cutillas P, Marshall JF, Cameron AJM. Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion. Cell Rep. 2022 Jan 25;38(4):110227. doi: 10.1016/j.celrep.2021.110227.
- Lindsay JO, Hind D, Swaby L, Berntsson H, Bradburn M, Bannur C U, Byrne J, Clarke C et al. (2024). Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial. The Lancet Gastroenterology & Hepatology vol. 9, (4) 333 - 345. doi: 10.1016/S2468-1253(23)00460-0.