It is well-established that the molecular mechanisms controlling gene expression are disrupted in cancer cells and work in this area has laid the foundations for targeted cancer therapies. We are interested in the regulatory pathways that control cell proliferation and cell migration and invasion and the events that disrupt this control in multiple types of cancer. Our focus is the Proline Rich Homeodomain protein (PRH/Hhex), an oligomeric transcription factor that regulates cell proliferation and cell behaviour in many cell types in the embryo and in the adult. Our most recent work has shown that PRH is an oncoprotein in bile duct cancer1, the second most common primary liver cancer.
Bile duct cancer is responsible for around 3000 deaths per year in the UK alone and new approaches to the treatment of this disease are required urgently. We have shown that PRH is not expressed in normal bile duct cells (cholangiocytes) whereas it is present in bile duct cancer cells (cholangiocarcinoma cells). Knockdown of PRH mRNA and protein expression in cholangiocarcinoma cells reduces the ability of these cells form tumours in a mouse model and reduces tumour growth. In contrast, expression of PRH in normal primary human cholangiocytes isolated from human liver, increases cell proliferation and induces cell migration and cell invasion. Genome-wide analysis of PRH regulated genes using RNA sequencing, and PRH binding sites using chromatin immunoprecipitation (ChIP) sequencing, reveals that PRH directly regulates many genes involved in the control of cell proliferation and cell phenotype plasticity.
The aim of this project is to investigate the tumour microenvironment in bile duct cancer to determine why PRH is expressed in cholangiocarcinoma cells but not in normal cholangiocytes. Our hypothesis is that PRH is aberrantly expressed in cholangiocytes in response to signals from the extracellular environment. These signals could include bile acids, cytokines (growth factors and other signalling molecules released by immune cells), and cell to cell signalling from stromal cells such as liver fibroblasts and infiltrating immune cells.
In this project we will perform an in-depth, spatially-resolved characterization of the cholangiocarcinoma tumour environment in human tissue samples using a novel multiplexed imaging and quantification system that allows us to simultaneously measure the expression of multiple immune cell markers and signalling molecules at the protein and mRNA level. This will allow us to correlate gene expression in cholangiocarcinoma cells with the immune and stromal cell types present within morphological regions of interest in tumours. We will also isolate primary bile duct cells and cholangiocarcinoma cells from human tissues using magnetic antibody-based technology and examine the communication between these cells and cholangiocytes and cholangiocarcinoma cells. This resource and expertise is uniquely available in the Jayaraman and Afford laboratories at the University of Birmingham where they have experience of growing bile duct cells, hepatocytes, and fibroblasts from human liver. Using whole genome transcriptomic approaches including RNA sequencing and global histone ChIP sequencing we will investigate the consequences of specific bile acids, cytokines, and co-culture with primary cells and on gene expression in normal cholangiocytes and cholangiocarcinoma cells.
This study will reveal the mechanisms that result in PRH expression in cholangiocarcinoma cells and the consequent effects on cell proliferation and cell behaviour. This will identify new targets for cancer therapy and provide new opportunities to improve the efficacy of cell-based immunotherapies.
Start dates are October, December, February and April each year
How to apply
To be considered for this studentship, please apply online at: https://www.nottingham.ac.uk/pgstudy/course/research/Medicine-PhD
Please include in your application:
• A detailed CV;
• Names and addresses of three referees;
• A covering letter highlighting your research experience/capabilities;
• At the top of your covering letter please put the name of your proposed supervisor and the title of the research
We will consider applications from self-funded prospective students with:
• a good biomedical or related degree, with interests in any of the areas outlined above,
• a good command of the English language (written and spoken) as outlined in the postgraduate prospectus,
• competence with computers and data handling,
• a source of funding to cover tuition fees and bench fees (note that tuition fees are different for Home and EU students than for International students). More information regarding fees can be found under the ‘Medicine’ heading at: View Website
1Kitchen, P., Lee, K.W., Clark, D., Lau, N., Lertsuwan, J., Sawasdichai, A., Satayavivad, J., Oltean, S., Afford, S., Gaston, K., and Jayaraman, P.S. (2020) A runaway PRH/HHEX-Notch3 positive feedback loop drives cholangiocarcinoma and determines response to CDK4/6 inhibition. Cancer Research, in press.