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. Overall design: 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.