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Nominating Supervisor: Dr Eileen Parkes

Second Supervisor: Dr Jan Rehwinkel

The Project

A key part of tackling cancer is understanding the tumour microenvironment, in particular the immune microenvironment. Cancers can gain a survival advantage by encouraging an inflammatory tumour microenvironment, which promotes tumour proliferation and invasion, leading to poor outcomes for patients with cancer.

The cGAS-STING pathway is crucial in cancer inflammation. Recently, new regulators of the cGAS-STING pathway were discovered which affect levels of 2’3’cGAMP (the STING agonist produced by cGAS) in the tumour microenvironment. Inhibitors of these are now being developed for clinical trials. However, it is not currently known how or where these novel cGAMP regulators are produced within the tumour microenvironment. Early data suggests that DNA damage is an important piece of this puzzle, and this project will aim to study this pathway in depth by:

(1)   Using DNA damaging agents, radiotherapy and cancer models with DNA repair defects to study the relationship between DNA damage and production of cGAMP regulators. Co-culture using immune cells, overexpression and inhibition of cGAMP regulation will determine the impact on tumour and immune cell behaviour.

(2)   Understanding where cGAMP regulators are produced in the tumour microenvironment. Using in vivo models of solid tumours treated with radiotherapy including those lacking DNA repair, single cell analysis will identify cells in the tumour microenvironment that are primarily responsible for regulating cGAMP and STING activation.

(3)   Using organoids and co-culture approaches to identify combination therapies where blocking cGAMP regulators alongside giving other immune-targeting treatments (such as viral approaches) could result in improved responses. These approaches will be studied in vivo and could be promising anti-cancer treatment strategies.

This project offers an opportunity for the student to study a key immune pathway working with experts in cGAS-STING signalling, with potential for translation to the clinical setting.

The Training

Students will partake in a comprehensive induction programme and structured lecture series. Hands-on support is provided on a daily basis by an assigned scientist within the Parkes group. The supervisory team bring combined expertise in molecular biology and DNA repair, STING pathway, innate immune signalling and in vivo modelling. A number of unique tumour models are available for this study, and molecular biology techniques including CRISPR-cas9, site-directed mutagenesis and immunoprecipitation will be familiar to the student at the completion of this project. Expertise in immune signalling and in vivo study will provide the student with the research experience required for a future career in tumour immunology. Access to transcriptomic datasets from solid tumours is available, and the student will be able to attend a comprehensive bioinformatics introductory course, providing them with the tools required for data analysis. The student will be encouraged to develop their own ideas around the work.

Publications

Parkes EE, Walker SM, Taggart LE, McCabe N, Knight L, McCloskey KD, Buckley NE, Savage KI, Salto-Tellez M, McQuaid S, Harte MT, Mullan PB, Harkin DP, Kennedy RD.  Activation of STING-dependent innate immune signalling by S-phase specific DNA damage in breast cancer.  Journal of the National Cancer Institute 2017; 109(1).

Bridgeman A, Maelfait J, Davenne T, Partidge T, Peng Y, Mayer A, Dong T, Kaever V, Borrow P, Rehwinkel J. Viruses transfer the antiviral second messenger cGAMP between cells. Science 2015; 349(6253):1228-32.