Dataset Information

EGAS00001004102-sc-2022-01-11T14:51:49Z - samples

ABSTRACT: SDH deficient renal cell carcinomas are a rare and recently defined subtype of kidney cancer, often associated with an inherited mutation in one of the SDH gene subunits. This dataset sought to understand the genomic events that underpin tumour formation, from putative cell of origin, characterisation of the tumour microenvironment, to the genomic evolution of these rare tumours. We performed whole genome and RNA sequencing of 4 patients with SDH deficient renal cell carcinomas, including one patient who had an additional paraganglioma. An addition patient in this cohort had the initial diagnosis revised to a clear cell renal cell carcinoma.

PROVIDER: EGAD00001008469 | EGA |

REPOSITORIES: EGA

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Project description:The tricarboxylic acid (TCA) cycle and electron transport chain (ETC) are key metabolic pathways required for cellular energy production. While loss of components in these pathways typically impairs cell survival, such defects can paradoxically promote tumorigenesis in certain cell types. One such example is loss of succinate dehydrogenase (SDH), which functions in both the TCA cycle and as Complex II of the ETC. Deleterious mutations in SDH subunits can cause pheochromocytoma and paraganglioma (PPGL), rare hereditary neuroendocrine tumors of chromaffin cells in the adrenal gland and the nerve ganglia, respectively. Why tumor formation upon SDH loss is limited to certain tissues remains unclear. We hypothesized that the metabolic and proteomic perturbations resulting from SDH loss are cell-type specific, favoring survival of chromaffin cells. To test this, we examined effects of SDH loss in two cell models, immortalized mouse chromaffin cells (imCCs) and immortalized mouse embryonic fibroblasts (iMEFs). We report that SDH loss differentially impacts the proteomes and acylproteomes of imCCs and iMEFs, with compartment-specific effects. Notably, SDH-loss imCCs show significant upregulation of mitochondrial proteins, including TCA cycle and fatty acid β-oxidation (FAO) enzymes, with pronounced downregulation of nuclear proteins. Both imCCs and iMEFs experience significant energy deficiency upon SDH loss, but FAO activity is uniquely increased in SDH-loss imCCs. While SDH loss increases both lysine-reactive acetyl-CoA and succinyl-CoA, SDH-loss imCCs and iMEFs show disproportionate hyperacetylation but mixed succinylation. Surprisingly, SDH-loss imCCs, but not iMEFs, display disproportionate hypoacetylation and hyposuccinylation of mitochondrial proteins. These findings suggest that cell type-specific adaptations to SDH loss underlie tissue-specific susceptibility to tumorigenesis and could illuminate therapeutic vulnerabilities of SDH-loss tumors.

Dataset Information

EGAS00001004102-sc-2022-01-11T14:51:49Z - samples

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