Investigating the impact of elevated circulating mitochondrial DNA on melanoma metastasis

Saad, Mona (2025) Investigating the impact of elevated circulating mitochondrial DNA on melanoma metastasis. Doctoral thesis, University of East Anglia.

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Abstract

Melanoma is the most aggressive, deadly form of skin malignancy. Despite only accounting for 5% of skin malignancy cases, it is the leading cause of death in the world of skin cancer. The prognosis of patients with metastatic melanoma is grim, with a 5-years survival rate of 5-19%. Melanoma affects people of working age, having physical, psychological, social and financial implications. Current diagnostic tools are invasive, anxiety inducing and costly. The clinical utility of biomarkers in melanoma remains unclear. This has been identified as one of the National Institute for Health and Care Excellence melanoma future research recommendations. Circulating DNA has been suggested to be a potential biomarker in cancer diagnosis with elevated circulating mitochondrial DNA (mtDNA) being associated with increased risk of cancers such as, breast, non-Hodgkin lymphoma and renal cell carcinoma. In melanoma, a handful of studies show increased mtDNA level is associated with the disease. However, no study has investigated mtDNA in the context of metastatic melanoma. In this thesis I investigate patient serum levels of cell-free mtDNA in metastatic melanoma and its potential role as a novel non-invasive biomarker. I also investigate the role of elevated mtDNA in promoting melanoma disease progression specifically investigating the liver as a known melanoma metastatic site.

My results indicated that circulating cell free mtDNA is elevated in metastatic melanoma in both human and melanoma engrafted mice. In our small sample size, the circulating cell free mtDNA level distinguished between the patient group who remained in remission compared to the group who developed a relapse post tumour resection. This highlights the potential role mtDNA may play as non-invasive biomarker in melanoma. Mechanistically, in mice, I show that melanoma engraftment mediated a downregulation of Stimulator of Interferon Genes (STING) in the liver. STING is known to play a role in innate immunity. The liver macrophages in melanoma engrafted mice exhibited a pro-tumour M2 like phenotype. To our knowledge this is the first data that has demonstrated that melanoma engraftment in mice resulted in the downregulation of STING in liver macrophages. Overall, the data presented provides an insight into the functional role that mtDNA plays in promoting an immunosuppressive microenvironment in melanoma facilitating disease progression.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Bethany Turner
Date Deposited:	05 Oct 2026 11:48
Last Modified:	05 Oct 2026 11:48
URI:	https://ueaeprints.uea.ac.uk/id/eprint/104721
DOI:

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