PhD studentship - Payam Gammage
Application closing date
Stipend - £21,000 per annum
Tuition fees are covered for home students.
Job descriptionThe impact of cancer-associated mitochondrial DNA mutations on tumour
All cancers bear somatic mutations within their genomes. The contribution of these mutations in the context of DNA contained within the nucleus is increasingly well-explored, however, in contrast the impact of prevalent mutations in the mitochondrial genome, present in more than 75% of all cancers remain largely unexplored and are an emerging frontier in cancer research.
Using large-scale patient sequencing and clinical data, our group and others have demonstrated that this major and understudied class of cancer-associated mutations contained within the mitochondrial DNA are associated with substantial impact on tumour characteristics and clinical outcomes Gorelick et al., 2021. Intriguingly, these impacts appear to be specific to the tissue lineage from which the tumour was initiated and the type of mutations found in the mtDNA, with colorectal cancers demonstrating the clearest signal.
Employing a complement of cellular and animal models of tumour biology alongside state-of-the-art mitochondrial genome engineering tools and metabolic analyses, this project will tease apart the lineage-specific impacts of highly recurrent cancer-associated mtDNA mutations on tumour metabolism, potentially revealing metabolic dependencies and therapeutic opportunities that have not been identified previously.
This project will make use of mitochondrially targeted zinc finger nuclease (mtZFN) and DddAtox cytidine base editor (DdCBE) technologies to manipulate mitochondrial genetics of murine cells across a range of tumour lineages. These cells will be studied in vitro using genetic and metabolic methods, such as single cell RNA sequencing, droplet digital PCR, microscale oximetry, metabolomics and isotope tracing. They will also be used for engrafting experiments in wild-type mice and resulting tumours will be characterised and analysed. Assessment of the tumour microenvironment will be carried out by histology and flow cytometry, non-invasive imaging of tumours using positron emission tomography of labelled metabolites and experimental treatment regimens employing pharmacological agents and radiotherapies.
For informal enquiries, please contact Dr Payam Gammage ([email protected]).