Defining and targeting mitochondrial dysfunction in cellular models of succinate dehydrogenase (SDH)-mutated tumours

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Context & research aimI am researching a group of tumours commonly referred to as PPGL (an abbreviation for Latin names Phaeochromocytoma and ParaGangLioma.) These tumours are mostly non-spreading "benign" tumours, but when they do spread to other parts of the body, they are defined as cancer. There are no good treatments for cancerous PPGL. In order to design better treatments, we need to understand what makes PPGL turn cancerous.The most common cause of cancerous PPGL is an inherited mutation (a "spelling mistake") in the genetic code for an enzyme called succinate dehydrogenase (SDH). This enzyme has 4 parts, named A, B, C, and D. A mutation in any one of these parts causes the enzyme to function poorly or not at all. Worryingly, patients with a B mutation are even more likely to get cancerous PPGL compared to patients whose tumour was caused by a mutation in a different SDH gene (A, C, or D.) My aim is to investigate the reason why SDH-B tumours are more likely than tumours with other SDH mutations to become cancerous. Background to research designEach cell has many "power houses" called mitochondria that host metabolic processes and generate fuel/energy for the cell. It is in mitochondria where SDH is found. SDH is an important enzyme for metabolism of the cell but when SDH malfunctions, there is accumulation of a chemical called succinate. High levels of succinate cause further changes in the cell that lead to tumour development. But while all SDH tumours have high levels of succinate, something else happens, mostly in the B tumours, to make them become cancerous. I propose that this other factor is related to the B mutation causing problems for mitochondria. Problems that arise in mitochondria can impact on its structure, its function in producing fuel, and its "life cycle". A side effect of metabolism in mitochondria is the generation of molecules (specifically, reactive oxygen species) that can damage DNA. Usually, our cells are very good at fixing this damage but if the repair mechanisms are faulty, then the DNA damage goes uncorrected, potentially leading to cancerous changes. We know that a particular repair mechanism can become faulty from high levels of succinate (the effect of SDH enzyme dysfunction), but we do not know if the repair mechanism is affected differently depending on which SDH part (A, B, C, or D) is mutated. To mimic what happens in patients, I am researching with cells that are the same except for one SDH part (A, B, C, or D) being deleted, which is the effect of a significant mutation. This is a subtle difference for a cell but one that can have serious consequences. If we can discover what happens in the cells lacking B to make them change from benign tumour cells to cancerous cells, then we can design treatments that block this change from happening. I will look for changes in different aspects of the mitochondria (structure, metabolic function, responses to cellular "stress", changes to its "life cycle") to see what is unique to cells that lack SDH-B, as occurs in patients with SDH-B tumours. I will test the effects of existing cancer treatments and metabolism treatments on these cells.ApplicationsI hope that findings from my research will be able to inform which treatments ought to be investigated further for cancerous PPGL, or form the basis for designing new treatments. My research may identify a target for developing techniques that detect cancerous PPGL earlier or that can predict precisely which PPGL will become cancerous.Progress in SDH PPGL research will help in the management of rarer tumours due to SDH mutations, such as particular types of kidney and stomach cancer. Findings related to the faulty DNA repair mechanism can be applied to other cancers where this occurs (e.g. breast, bowel) and there may be implications for non-cancerous diseases of mitochondria.