Role of copper in progression of clear cell renal cell carcinoma [Spatial transcriptomics]

Copper (Cu) is an essential trace element required for mitochondrial respiration. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis and promotes tumor growth and progression of clear cell renal cell carcinoma (ccRCC). Late-stage ccRCCs accumulate Cu and allocate it to cytochrome c oxidase stimulating bioenergy production. Cu induces TCA cycle-dependent oxidation of glucose and its utilization for biosynthesis of a glutathione pool that protects against H2O2 generated during mitochondrial respiration, therefore coordinating bioenergy production with redox protection. Single cell transcriptomics determined induction of mitochondrial electron transport chain, expression of NRF2 targets and glutathione biosynthesis, and decrease in HIF activity, the hallmark of ccRCC, during disease progression. Spatial transcriptomics identified that cancer cells with proliferative phenotype are embedded in clusters of cells with oxidative metabolism supporting effects of metabolic states on ccRCC progression. Our work establishes novel vulnerabilities with potential for therapeutic interventions in ccRCC. We have analyzed 5 spatial transcriptomic tissue sections from simple stage-3 clear cell Renal Cell Carcinoma tumors. FFPE tumor sections were placed on Visium gene expression slide and stained for morphological context using H&E. Spatial transcriptomics was performed by 10x Genomics Visium Certified Service Providers. ccRCC tissues were obtained from UC Tumor Bank. The results were processed by spaceRanger software to acquire expression matrix of each sample. Spatial transcriptomics images and expression files.

铜（Cu）是线粒体呼吸所需的必需微量元素。本研究证实，铜可介导生物能量代谢、生物合成与氧化还原稳态的协同重塑，并促进透明细胞肾细胞癌（clear cell renal cell carcinoma, ccRCC）的肿瘤生长与疾病进展。晚期ccRCC组织会出现铜富集现象，并将铜分配至细胞色素c氧化酶，从而刺激生物能量生成。铜可诱导三羧酸循环（tricarboxylic acid cycle, TCA）依赖的葡萄糖氧化，并将葡萄糖用于谷胱甘肽池的生物合成，以抵御线粒体呼吸过程中产生的过氧化氢（H₂O₂），从而实现生物能量生成与氧化还原保护的协同调控。单细胞转录组学分析显示，在疾病进展过程中，线粒体电子传递链相关基因表达上调、核因子E2相关因子2（nuclear factor erythroid 2-related factor 2, NRF2）靶基因与谷胱甘肽生物合成相关基因表达升高，而缺氧诱导因子（hypoxia-inducible factor, HIF）活性降低——这正是ccRCC的标志性特征。空间转录组学分析发现，具有增殖表型的癌细胞嵌入于以氧化代谢为特征的细胞簇中，进一步证实了代谢状态对ccRCC进展的调控作用。本研究揭示了ccRCC中具有治疗干预潜力的新型易感靶点。本研究共分析了5例单纯性3期透明细胞肾细胞癌肿瘤的空间转录组组织切片。福尔马林固定石蜡包埋（formalin-fixed paraffin-embedded, FFPE）的肿瘤切片被置于Visium基因表达芯片上，并通过苏木精-伊红（hematoxylin-eosin, H&E）染色以获取形态学背景信息。空间转录组测序由10x Genomics公司的Visium认证服务提供商完成。本研究的ccRCC组织均取自UC肿瘤库。测序结果通过spaceRanger软件进行处理，以获取每个样本的基因表达矩阵。本数据集包含空间转录组学图像与基因表达文件。