Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma

Czyzyk-Krzeska, M.; Bischoff, M. E.; Shamsaei, B.; Yang, J.; Secic, D.; Vemuri, B.; Reisz, J. A.; D'Alessandro, A.; Bartolacci, C.; Adamczyk, R.; Schmidt, L.; Wang, J.; Martines, A.; Biesiada, J.; Vest, K. E.; Scaglioni, P. P.; Plas, D. R.; Patra, K. C.; Gulati, S.; Figueroa, J. L.; Meller, J.; Cunningham, J. T.

doi:10.1101/2024.01.16.575895

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bioRxiv · 10.1101/2024.01.16.575895

Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma

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Abstract

Copper (Cu) is an essential trace element required for mitochondrial respiration. Late-stage clear cell renal cell carcinoma (ccRCC) accumulates Cu and allocates it to mitochondrial cytochrome c oxidase. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis, promoting tumor growth and progression of ccRCC. Specifically, Cu induces TCA cycle-dependent oxidation of glucose and its utilization for glutathione biosynthesis to protect against H2O2 generated during mitochondrial respiration, therefore coordinating bioenergy production with redox protection. scRNA-seq determined that ccRCC progression involves increased expression of subunits of respiratory complexes, genes in glutathione and Cu metabolism, and NRF2 targets, alongside a decrease in HIF activity, a hallmark of ccRCC. Spatial transcriptomics identified that proliferating cancer cells 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/575895v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@14e1b89org.highwire.dtl.DTLVardef@f1c83forg.highwire.dtl.DTLVardef@191aff8org.highwire.dtl.DTLVardef@1b7ccd1_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIAccumulation of copper is associated with progression and relapse of ccRCC and drives tumor growth. C_LIO_LICu accumulation and allocation to cytochrome c oxidase (CuCOX) remodels metabolism coupling energy production and nucleotide biosynthesis with maintenance of redox homeostasis. C_LIO_LICu induces oxidative phosphorylation via alterations in the mitochondrial proteome and lipidome necessary for the formation of the respiratory supercomplexes. C_LIO_LICu stimulates glutathione biosynthesis and glutathione derived specifically from glucose is necessary for survival of CuHi cells. Biosynthesis of glucose-derived glutathione requires activity of glutamyl pyruvate transaminase 2, entry of glucose-derived pyruvate to mitochondria via alanine, and the glutamate exporter, SLC25A22. Glutathione derived from glucose maintains redox homeostasis in Cu-treated cells, reducing Cu-H2O2 Fenton-like reaction mediated cell death. C_LIO_LIProgression of human ccRCC is associated with gene expression signature characterized by induction of ETC/OxPhos/GSH/Cu-related genes and decrease in HIF/glycolytic genes in subpopulations of cancer cells. Enhanced, concordant expression of genes related to ETC/OxPhos, GSH, and Cu characterizes metabolically active subpopulations of ccRCC cells in regions adjacent to proliferative subpopulations of ccRCC cells, implicating oxidative metabolism in supporting tumor growth. C_LI

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Czyzyk-Krzeska, M., Bischoff, M. E., Shamsaei, B., Yang, J., Secic, D., Vemuri, B., Reisz, J. A., D'Alessandro, A., Bartolacci, C., Adamczyk, R., Schmidt, L., Wang, J., Martines, A., Biesiada, J., Vest, K. E., Scaglioni, P. P., Plas, D. R., Patra, K. C., Gulati, S., Figueroa, J. L., Meller, J., Cunningham, J. T.. 2024-01-20. Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma. https://doi.org/10.1101/2024.01.16.575895

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