Metabolic Rewiring Is Required for Epithelial–Mesenchymal Transition Free

Alterations in cellular metabolism have been shown to promote cancer cell proliferation, but the role of metabolic changes in promoting cancer cell aggressiveness remains poorly understood. Using mRNA expression profiles of metabolic genes in cancer cell lines, Shaul and colleagues identified five distinct groups of cell lines, including a mixed-lineage group that consisted of multiple types of high-grade malignancies expressing mesenchymal markers. In addition, compared with other groups of cells, this mixed-lineage group of cell lines exhibited elevated expression of a 44-gene mesenchymal metabolic signature (MMS), which was upregulated following induction of the epithelial–mesenchymal transition (EMT) program in human mammary epithelial cells. Sixteen MMS genes, including dihydropyrimidine dehydrogenase (DPYD), which encodes a pyrimidine-degrading enzyme, were found to be critical for EMT induction using a FACS-based RNAi screen. Depletion of DPYD did not affect cell proliferation, but suppressed Twist-induced expression of mesenchymal markers, reduced mammosphere formation, cell migration, and invasion, and impaired tumor cell extravasation in vivo. Ectopic expression of wild-type DPYD but not a catalytically attenuated DPYD mutant rescued EMT induction, illustrating that DPYD enzymatic activity is essential for EMT. Consistent with this idea, levels of dihydropyrimidines, the metabolic products of DPYD activity, were increased during EMT. Reduction of dihydropyrimidine levels decreased the percentage of cells with a mesenchymal profile, whereas the addition of dihydropyrimidines restored EMT induction in the absence of DPYD, suggesting that intracellular accumulation of these DPYD metabolic products plays a key role in the EMT program. Although additional work is needed to characterize the function of dihydropyrimidines in the acquisition of the mesenchymal phenotype, these results identify metabolic processes that are required for EMT and suggest that DPYD may contribute to cancer cell aggressiveness and metastasis.

Shaul YD, Freinkman E, Comb WC, Cantor JR, Tam WL, Thiru P, et al. Dihydropyrimidine accumulation is required for the epithelial–mesenchymal transition. Cell 2014;158:1094–1109.