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

琥珀酸脱氢酶 (SDH) 突变肿瘤细胞模型中线粒体功能障碍的定义和靶向

• 批准号: MR/W001101/1
• 负责人: Eugenie Lim
• 金额: $ 41.79万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW001101%2F1
• 关键词: Defining; targeting; mitochondrial; dysfunction; cellular

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.

背景和研究目的我正在研究一组通常被称为PPGL的肿瘤（拉丁名称Phaeochromocytoma和ParaGangLioma的缩写）。这些肿瘤大多是非扩散性的“良性”肿瘤，但当它们扩散到身体的其他部位时，它们被定义为癌症。对于癌性PPGL没有好的治疗方法。为了设计更好的治疗方法，我们需要了解PPGL癌变的原因。PPGL癌变最常见的原因是一种叫做琥珀酸脱氢酶（SDH）的遗传密码发生了遗传突变（一种“拼写错误”）。这种酶有4个部分，分别命名为A、B、C和D。这些部分中的任何一个突变都会导致酶功能低下或根本不起作用。令人担忧的是，与由不同SDH基因（A、C或D）突变引起的肿瘤患者相比，具有B突变的患者更有可能患癌性PPGL。我的目的是调查为什么SDH-B肿瘤比其他SDH突变的肿瘤更容易癌变。研究设计的背景每个细胞都有许多称为线粒体的“发电厂”，它们主持代谢过程并为细胞产生燃料/能量。SDH是细胞代谢的重要酶，但当SDH功能失常时，就会积累一种叫做琥珀酸的化学物质。高水平的琥珀酸会导致细胞的进一步变化，从而导致肿瘤的发展。但是，尽管所有SDH肿瘤都有高水平的琥珀酸，但其他一些事情发生了，主要是在B肿瘤中，使它们成为癌症。我认为这另一个因素与B突变引起线粒体问题有关。线粒体中出现的问题可能会影响其结构，其产生燃料的功能及其“生命周期”。线粒体中代谢的副作用是产生可以损伤DNA的分子（特别是活性氧）。通常情况下，我们的细胞非常善于修复这种损伤，但如果修复机制有缺陷，那么DNA损伤就无法得到纠正，可能导致癌变。我们知道，一个特定的修复机制可能会成为故障从高水平的琥珀酸（SDH酶功能障碍的影响），但我们不知道是否修复机制受到不同的影响取决于哪个SDH部分（A，B，C，或D）突变。为了模拟患者的情况，我正在研究除了SDH的一个部分（A，B，C或D）被删除之外的相同细胞，这是一个重大突变的影响。这对细胞来说是一个微妙的差异，但可能会产生严重的后果。如果我们能发现缺乏B的细胞中发生了什么，使它们从良性肿瘤细胞变成癌细胞，那么我们就可以设计出阻止这种变化发生的治疗方法。我将寻找线粒体不同方面的变化（结构，代谢功能，对细胞“压力”的反应，其“生命周期”的变化），以了解缺乏SDH-B的细胞的独特之处，正如SDH-B肿瘤患者所发生的那样。我将测试现有的癌症治疗和代谢治疗对这些细胞的影响。应用我希望我的研究结果能够告知哪些治疗应该进一步研究癌性PPGL，或形成设计新治疗方法的基础。我的研究可能会为开发早期检测癌性PPGL或精确预测哪种PPGL会癌变的技术确定一个目标。SDH PPGL研究的进展将有助于管理由于SDH突变引起的罕见肿瘤，如特定类型的肾癌和胃癌。与错误的DNA修复机制相关的发现可以应用于发生这种情况的其他癌症（例如乳腺癌，肠癌），并且可能对线粒体的非癌性疾病有影响。

项目成果

Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort.

• DOI: 10.1111/cen.14639
• 发表时间: 2022-10
• 期刊: Clinical endocrinology
• 影响因子: 3.2

Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma.

• DOI: 10.3389/fendo.2022.1070074
• 发表时间: 2022
• 期刊: FRONTIERS IN ENDOCRINOLOGY
• 影响因子: 5.2
• 作者: Mellid, Sara;Gil, Eduardo;Leton, Rocio;Caleiras, Eduardo;Honrado, Emiliano;Richter, Susan;Palacios, Nuria;Lahera, Marcos;Galofre, Juan C.;Lopez-Fernandez, Adria;Calatayud, Maria;Herrera-Martinez, Aura D.;Galvez, Maria A.;Matias-Guiu, Xavier;Balbin, Milagros;Korpershoek, Esther;Lim, Eugenie S.;Maletta, Francesca;Lider, Sofia;Fliedner, Stephanie M. J.;Bechmann, Nicole;Eisenhofer, Graeme;Canu, Letizia;Rapizzi, Elena;Bancos, Irina;Robledo, Mercedes;Cascon, Alberto
• 通讯作者: Cascon, Alberto

Distortion in transmission of pathogenic SDHB- and SDHD-mutated alleles from parent to offspring.

致病性 SDHB 和 SDHD 突变等位基因从父母到后代的传播扭曲。

• DOI: 10.1530/erc-22-0233
• 发表时间: 2023
• 期刊: Endocrine-related cancer
• 影响因子: 3.9
• 作者: Davidoff DF

A comprehensive characterisation of phaeochromocytoma and paraganglioma tumours through histone protein profiling, DNA methylation and transcriptomic analysis genome wide.

• DOI: 10.1186/s13148-023-01598-3
• 发表时间: 2023-12-20
• 期刊: Clinical epigenetics
• 影响因子: 5.7