Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, Texas, United States.
Genomic Medicine, UT MD Anderson Cancer Center, Houston, Texas, United States.
Invest Ophthalmol Vis Sci. 2019 Oct 1;60(13):4187-4195. doi: 10.1167/iovs.19-28082.
Metastatic 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.
We 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.
We 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.
Our 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.
转移性葡萄膜黑色素瘤（UM）预后极差，且缺乏有效治疗方法。尽管在治疗皮肤黑色素瘤方面取得了显著进展，但 UM 仍然对化疗、小分子激酶抑制剂和免疫治疗具有抗性。
我们评估了 31 种癌症类型的 9858 个肿瘤中的两组氧化磷酸化（OxPhos）基因。使用 OxPhos 抑制剂来描述高度转移性三倍体 3（M3）UM 的不同代谢编程。进行 Seahorse 分析和全局代谢组学分析，以确定代谢脆弱性。对 UM TCGA 数据集进行分析，以确定 M3 和非 M3 UM 中关键 OxPhos 效应物的表达。我们使用靶向 SDHA 敲低来确定 SDHA 在赋予 M3 UM 对 OxPhos 抑制的抗性中的作用。
我们发现 UM 的 OxPhos 水平中位数最高，并表明 M3 UM 表现出独特的代谢特征。M3 UM 表现出明显的琥珀酸水平降低，并且 SDHA 水平显著升高，SDHA 是一种通过氧化（降低）琥珀酸将三羧酸循环与 OxPhos 偶联的酶。我们表明，SDHA 高的 M3 UM 具有关键 OxPhos 分子的高表达，具有丰富的线粒体储备呼吸能力，并且对 OxPhos 拮抗作用具有抗性，这种抗性可以通过 SDHA 敲低来逆转。
我们的研究在预后不良的 M3 UM 中确定了一个关键的代谢程序。除了由于 SDHA 升高而导致的线粒体功能能力增强外，M3 UM 的 SDHA 高还介导对治疗的抗性，靶向治疗可逆转这种抗性。
