Dr Payam Gammage & Prof Owen Sansom
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 or further details on the project, please contact Dr Payam Gammage (email@example.com)
Kim M, Mahmood M, Reznik E, Gammage PA. Mitochondrial DNA is a major source of driver mutations in cancer. Trends in Cancer. 2022;
Ganly I, Liu EM, Kuo F, Makarov V, Dong Y, Park J, Gong Y, Gorelick AN, Knauf JA, Benedetti E, Tait-Mulder J, Morris LGT, Fagin JA, Intlekofer AM, Krumsiek J, Gammage PA, Ghossein R, Xu B, Chan TA, Reznik E. Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hürthle cell carcinoma. Sci Adv. 2022 Jun 24;8(25):eabn9699. doi: 10.1126/sciadv.abn9699. Epub 2022 Jun 22. PMID: 35731870; PMCID: PMC9216518.
Rabas N, Palmer S, Mitchell L, Ismail S, Gohlke A, Riley JS, Tait SWG, Gammage P, Soares LL, Macpherson IR, Norman JC. PINK1 drives production of mtDNA-containing extracellular vesicles to promote invasiveness. J Cell Biol. 2021 Dec 6;220(12):e202006049. doi: 10.1083/jcb.202006049. Epub 2021 Oct 8. PMID: 34623384.
Gorelick AN, Kim M, Chatila WK, La K, Hakimi AA, Berger MF, Taylor BS, Gammage PA, Reznik E. Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA. Nat Metab. 2021 Apr;3(4):558-570. doi: 10.1038/s42255-021-00378-8. Epub 2021 Apr 8. PMID: 33833465.
Jackson CB, Turnbull DM, Minczuk M, Gammage PA. Therapeutic Manipulation of mtDNA Heteroplasmy: A Shifting Perspective. Trends Mol Med. 2020 Jul;26(7):698-709. doi: 10.1016/j.molmed.2020.02.006. Epub 2020 Mar 26. PMID: 32589937.
Bacman SR, Gammage PA, Minczuk M, Moraes CT. Manipulation of mitochondrial genes and mtDNA heteroplasmy. Methods Cell Biol. 2020;155:441-487. doi: 10.1016/bs.mcb.2019.12.004. Epub 2020 Jan 20. PMID: 32183972.
Andreazza S, Samstag CL, Sanchez-Martinez A, Fernandez-Vizarra E, Gomez-Duran A, Lee JJ, Tufi R, Hipp MJ, Schmidt EK, Nicholls TJ, Gammage PA, Chinnery PF, Minczuk M, Pallanck LJ, Kennedy SR, Whitworth AJ. Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila. Nat Commun. 2019 Jul 23;10(1):3280. doi: 10.1038/s41467-019-10857-y. PMID: 31337756; PMCID: PMC6650417.