Targeting macrophage-epithelial interactions as drivers of tumour initiation in inflammatory liver disease.

The PhD studentship is open to UK applicants only

Supervisors

• Dr Ed Jarman
• Professor Karen Brown kb20@le.ac.uk
• Dr Ning Wang

Project:

Background:

Cholangiocarcinoma (CCA) is a group of aggressive malignancies that arise within the liver and extrahepatic bile ducts. There are a number of risk factors for the development of CCA and in the UK the most prevalent factor is a diagnosis of Primary Sclerosing Cholangitis (PSC), where patients suffer from chronic bile duct damage, inflammation and repair. As in other cancers, inflammation provides a permissive background on which cancer can form, however the combinatorial role for driver mutations in epithelial cells and inflammatory signals remains unclear.
Previous work using mouse models of PSC-to-CCA transition has identified transcriptional changes corresponding to the earliest epithelial states as these cells become dysplastic tumours. These states, which are driven by the combination of early oncogenic drivers and liver inflammation, are characterised by the aberrant epithelial expression of COX2, which drives local immune cell recruitment. We now aim to address whether these processes represent specific, pharmacologically tractable mechanisms that promote the transition of chronic disease into cancer in patients with PSC or other inflammatory diseases with known risk of CCA. 
By understanding these earliest processes in tumour initiation, we hope to establish novel approaches for the risk stratification and targeted prevention of CCA in patients with inflammatory liver disease. 

Research Plan:

This project will utilise tissue from patients with inflammatory liver disease and leverage local expertise in patient ex-vivo cultures to assess the presence and functional role of epithelial cell states which have previously been shown to represent early neoplastic transition in bile ducts. Using Primary Sclerosing Cholangitis as an exemplar and techniques including multiplex immunofluorescence, flow cytometry, and mining of publicly available datasets, we will identify and characterise COX2-positive epithelial cells in the inflamed liver to ask how these cells pattern their local immune environment. We will characterise the local recruitment of macrophages and other immune cell types to COX2 expressing epithelial cells and investigate crosstalk between these two cell types. Finally, using CRISPR-editing of cholangiocyte cell lines and biliary epithelial organoids we will ask how signals from recruited immune cells are interpreted by mutant epithelial populations to drive neoplastic growth.

Expected outcomes and impact:

We expect that this project will provide a clearer understanding of the functional role of COX2 expression by mutant epithelial cells in patients with inflammatory pre-cancerous liver disease. By interpreting how these cells pattern their immune environment and assessing immune cell heterogeneity across patients and inflammatory aetiologies, we will better understand which patients with PSC may benefit from COX2 inhibition through low-dose aspirin, identify novel approaches for targeting pre-neoplastic transitionary states as a preventative approach for CCA, and address whether other inflammatory liver conditions may promote CCA through analogous mechanisms.
 
References
• Alonso-Curbelo, D. et al. A gene-environment-induced epigenetic program initiates tumorigenesis. Nature 590, 642–648 (2021).
• Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, Cardinale V, Carpino G, Andersen JB, Braconi C, Calvisi DF, Perugorria MJ, Fabris L, Boulter L, Macias RIR, Gaudio E, Alvaro D, Gradilone SA, Strazzabosco M, Marzioni M, Coulouarn C, Fouassier L, Raggi C, Invernizzi P, Mertens JC, Moncsek A, Ilyas SI, Heimbach J, Koerkamp BG, Bruix J, Forner A, Bridgewater J, Valle JW, Gores GJ. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588. doi: 10.1038/s41575-020-0310-z. Epub 2020 Jun 30. PMID: 32606456; PMCID: PMC7447603.
• Caronni, N. et al. IL-1β+ macrophages fuel pathogenic inflammation in pancreatic cancer. Nature 623, 415–422 (2023).
• Song, J. et al. Cholangiocarcinoma in Patients with Primary Sclerosing Cholangitis (PSC): a Comprehensive Review. Clin. Rev. Allergy Immunol. 58, 134–149 (2020).
• Trivedi, P. J., Bowlus, C. L., Yimam, K. K., Razavi, H. & Estes, C. Epidemiology, Natural History, and Outcomes of Primary Sclerosing Cholangitis: A Systematic Review of Population-based Studies. Clin. Gastroenterol. Hepatol. 20, 1687-1700.e4 (2022).
• Zelenay, S. et al. Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity. Cell 162, 1257–1270 (2015).