Research Opportunities

The tumour suppressor p53 is encoded by the most mutated gene in human cancers and there is extensive knowledge of its vital role in tumour suppression. However, the contribution of p53 to immune surveillance is less well understood. Cancer initiation and progression is influenced by inflammation, and it is increasingly important to understand interactions between inflammatory and tumourigenic pathways to improve cancer prevention and patient responses to immunotherapy. p53 activity is known to intersect with key inflammatory signalling pathways, including NFB, AP1, MAPK and JAK/STAT, suggesting p53 could have a pivotal role in immune surveillance. To expand knowledge in this important area, this project will investigate crosstalk between the p53 pathway and inflammation.

The project will use cutting edge technologies, including ex vivo 3D organoid co-culture models, to study interactions between cancer-initiating epithelial cells and immune cells. It will also harness recent advances in RNA-sequencing, single cell analysis and ChIP-sequencing, as well as a broad range of molecular cell biology techniques, to address the crosstalk between p53 and inflammation. The student will be able to leverage access to expertise and clinical samples in chronic inflammatory conditions – such as Barrett’s Oesophagus – that predispose patients to cancer. Oesophageal cancer and stomach cancer may be used as exemplar cancer types; these cancers have important unmet clinical needs and strong links to inflammation. This project may also extend to crosstalk of p53 with the immune system, such as in the context of immunotherapy for cancer: an emerging therapeutic strategy that is showing great success in some patients. The study will offer exciting opportunities to understand the details of the relationship between p53 and inflammation, which will be crucial for developing new approaches for early intervention to prevent cancer progression and for understanding responses to therapy.

In order to maintain homeostasis in response to environmental changes such as nutrient availability, eukaryotic cells have evolved intricate mechanisms to quickly increase or decrease the activity of fundamental processes such as gene expression, protein expression and degradation. Indeed, several metabolites act as cofactors for important cellular enzymes that regulate e.g. chromatin state and serve as templates for posttranslational modifications flagging proteins for proteolysis via the ubiquitin-proteasome system. Consequently, the identification of metabolites and complementary binding domains has broadened our understanding of human physiology and contributed to the development of new medicines to treat malignant and inflammatory disease. The aim of this project is to systematically map protein-metabolite interactions on a proteome-wide scale by combining the development of specific metabolite-inspired affinity reagents with unbiased approaches such as thermal profiling to dissect metabolite signalling in the context of protein degradation pathways in various cell types. Applicants will have the opportunity to take advantage of a unique combination of synthetic organic chemistry and cell biology techniques to identify new potential drug targets and develop first-in-class ligands for key regulators of protein homeostasis.