Characterization of the Usage of the Serine Metabolic Network in Human Cancer

• Reconstruction of the SGOC metabolic network was carried out in cancer and normal tissues
• Most pathways show heterogeneity across and within tumor and normal tissue types
• Serine flux simultaneously distributes to nucleotides, NAPDH, and redox metabolism
• Flux analysis of serine shows that gene expression patterns can predict flux

SummaryThe serine, glycine, one-carbon (SGOC) metabolic network is implicated in cancer pathogenesis, but its general functions are unknown. We carried out a computational reconstruction of the SGOC network and then characterized its expression across thousands of cancer tissues. Pathways including methylation and redox metabolism exhibited heterogeneous expression indicating a strong context dependency of their usage in tumors. From an analysis of coexpression, simultaneous up- or downregulation of nucleotide synthesis, NADPH, and glutathione synthesis was found to be a common occurrence in all cancers. Finally, we developed a method to trace the metabolic fate of serine using stable isotopes, high-resolution mass spectrometry, and a mathematical model. Although the expression of single genes didn’t appear indicative of flux, the collective expression of several genes in a given pathway allowed for successful flux prediction. Altogether, these findings identify expansive and heterogeneous functions for the SGOC metabolic network in human cancer.

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