Neutrophil biology in chromosomally unstable cancer
Primary Supervisor: Dr Eileen Parkes
Second Supervisor: Professor Eric O'Neill
Project Overview
Chromosomal instability is a feature of cancer that is associated with poor prognosis and treatment resistance, including to immune checkpoint blockade. A feature of chromosomally unstable cancers is that they constitutively stimulate the innate immune cGAS-STING pathway, via aberrant cytosolic DNA often contained in structures called micronuclei.
Our focus has been on oesophagogastric cancer (OGC) - this is an aggressive cancer, increasing in incidence in the UK and US, including in younger people with ~50% patients dying with 1 year of diagnosis. A characteristic feature of OGC is high rates of chromosomal instability (CIN). Our preliminary data suggests an important role for myeloid cells, particularly neutrophils, in mediating tumour growth and resistance in these cancers.
Translation of CIN-targeting therapies to the clinical setting has been hindered by a lack of suitable mouse models, especially for OGC. Using in-house genetic tools and expertise, the candidate will develop and validate a novel series of CIN-low to CIN-high syngeneic models of gastro-oesophageal cancer.
Aims
1 – Characterise the tumour microenvironment of CIN-high oesophagogastric cancer in murine models
2 –Investigate the impact of targeting myeloid cells in the tumour microenvironment, both alone and in combination with other immune-activating strategies
3 – Correlate findings in human cancer tissue using disaggregation of fresh tumour samples and matched whole blood to identify subsets of myeloid cells in the tumour microenvironment that are responsible for the aggressive, treatment resistant phenotype.
Training Opportunities
The successful candidate will be trained in molecular biology techniques, including cloning and genetic editing. Candidates will receive training in in vivo handling techniques, as well as flow cytometry for immune analysis of the tumour microenvironment and multiplex immunofluorescence. Candidates will be given the opportunity to develop or improve their bioinformatic skills via attendance at bioinformatic training courses, and will generate novel transcriptomic datasets from their work in vivo and ex vivo.
Relevant Publications