Elevated Endogenous SDHA Drives Pathological Metabolism in Highly Metastatic Uveal Melanoma

Abstract

PurposeMetastatic uveal melanoma (UM) has a very poor prognosis and no effective therapy. Despite remarkable advances in treatment of cutaneous melanoma, UM remains recalcitrant to chemotherapy, small-molecule kinase inhibitors, and immune-based therapy.MethodsWe assessed two sets of oxidative phosphorylation (OxPhos) genes within 9858 tumors across 31 cancer types. An OxPhos inhibitor was used to characterize differential metabolic programming of highly metastatic monosomy 3 (M3) UM. Seahorse analysis and global metabolomics profiling were done to identify metabolic vulnerabilities. Analyses of UM TCGA data set were performed to determine expressions of key OxPhos effectors in M3 and non-M3 UM. We used targeted knockdown of succinate dehydrogenase A (SDHA) to determine the role of SDHA in M3 UM in conferring resistance to OxPhos inhibition.ResultsWe identified UM to have among the highest median OxPhos levels and showed that M3 UM exhibits a distinct metabolic profile. M3 UM shows markedly low succinate levels and has highly increased levels of SDHA, the enzyme that couples the tricarboxylic acid cycle with OxPhos by oxidizing (lowering) succinate. We showed that SDHA-high M3 UM have elevated expression of key OxPhos molecules, exhibit abundant mitochondrial reserve respiratory capacity, and are resistant to OxPhos antagonism, which can be reversed by SDHA knockdown.ConclusionsOur study has identified a critical metabolic program within poor prognostic M3 UM. In addition to the heightened mitochondrial functional capacity due to elevated SDHA, M3 UM SDHA-high mediate resistance to therapy that is reversible with targeted treatment.

High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells

“…Altered metabolism is a hallmark of cancer [ 46 ] and oxidative phosphorylation has emerged as a therapeutic strategy [ 47 ]. Comparing 31 tumour types, UM ranked amongst the tumours with the highest oxidative phosphorylation signature [ 48 ]. To determine if the effects of CysLT 1 antagonists were due to altered metabolism in UM cells, the Seahorse Assay was performed assessing two key metabolic pathways: oxidative phosphorylation and glycolysis.…”

Additive Role of Immune System Infiltration and Angiogenesis in Uveal Melanoma Progression

“…These metabolic pathways have already been linked to immune-resistance to checkpoint inhibitors in different studies [ 34 , 36 , 37 , 38 ]. Interestingly, a recent study has shown that UM is among the tumors with the highest oxidative phosphorylation gene expression and correlates with prognosis in primary UM [ 39 ]. Our group has recently made the same observation in MUM patients [ 40 ].…”

Comprehensive analysis of cutaneous and uveal melanoma liver metastases

“…Gene set enrichment analyzes (GSEA) on DEGs and PC1/PC2 ( figure 4E, online supplemental figure 3) demonstrated increased expression of hallmark gene sets involved in metabolic pathways, such as oxidative phosphorylation (OXPHOS), xenobiotic metabolism and fatty acid metabolism in UM. It has previously been described that UM is ranked among the tumors with the highest OXPHOS signature, 62 and this property has been associated with invasiveness and drug resistance. 63 Pathways upregulated in CM involved proliferation (mitotic spindle, E2F targets, MYC targets and G2M checkpoint) and immune pathway (tumornecrosefactor-alfa (TNFA) signaling via NFKB) ( figure 4E).…”