Targeting the STING inflammation link in cancer
Inflammation and cancer have a complicated relationship. An immune reaction is essential to prevent cancer, but at some point the cancer/immune response tips into a chronic sustained inflammation which benefits cancer growth and spread. Key pathways in maintaining and sustaining inflammation include the cGAS-STING pathway and the inflammasome pathway. 2’3’cGAMP can stimulate both pathways, and may stimulate these pathways differently in various cells in the tumour microenvironment. 2’3’cGAMP production can be stimulated by radiotherapy. A number of uptake channels for 2’3’cGAMP in macrophages, lymphocytes and endothelial cells have been identified. However, how these channels are distributed or operate in the context of cancer, of the impact of 2’3’cGAMP uptake on various cells in the tumour microenvironment, remains unclear.
This project will address the following questions:
(1) The expression of known and emerging 2’3’cGAMP uptake channels in cancer: Using transcriptomic data (from publicly available and internal datasets) the relationship between 2’3’cGAMP import channels and cancer outcome will be explored. Using CRISPRko in cell lines such as THP1 monocytes and Hs68 fibroblasts, the impact of alteration of expression of these pathways will be explored, including effect on polarisation, migration and invasion with/without DNA damaging radiation therapy treatment. This will involve molecular biology techniques including CRISPR cas9 gene editing.
(2) Identification of import/export channels in cancer associated fibroblasts. A fibroblast cell line will be treated with TGFβ to stimulate differentiation to a cancer-associated fibroblast phenotype. A targeted screen will be performed in these conditions to identify important channels in the modulation of 2’3’cGAMP import.
(3) Modification of important transport channels identified in aim (1) and (2) will be performed using in vivo models, including syngeneic cell lines. Injections of modified fibroblasts with cancer cell lines will be performed in vivo to determine the effect on (a) cancer spread and (b) response to therapy.
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. The student will be encouraged to develop their own ideas around the work in a supportive environment.
- 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.