Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition

It is increasingly appreciated that oncogenic transformation alters cellular metabolism to facilitate cell proliferation, but less is known about the metabolic changes that promote cancer cell aggressiveness. Here, we analyzed metabolic gene expression in cancer cell lines and found that a set of high-grade carcinoma lines expressing mesenchymal markers share a unique 44 gene signature, designated the “mesenchymal metabolic signature” (MMS). A FACS-based shRNA screen identified several MMS genes as essential for the epithelial-mesenchymal transition (EMT), but not for cell proliferation. Dihydropyrimidine dehydrogenase (DPYD), a pyrimidine-degrading enzyme, was highly expressed upon EMT induction and was necessary for cells to acquire mesenchymal characteristics in vitro and for tumorigenic cells to extravasate into the mouse lung. This role of DPYD was mediated through its catalytic activity and enzymatic products, the dihydropyrimidines. Thus, we identify metabolic processes essential for the EMT, a program associated with the acquisition of metastatic and aggressive cancer cell traits.United States. National Institutes of Health (RO1 CA103866)United States. National Institutes of Health (AI047389)United States. National Institutes of Health (K99 CA168940)American Cancer Society (PF-12-099-01-TGB)American Cancer Society (PF-13-356-01-TBE)United States. Department of Defense (BC123066)United States. National Institutes of Health (CA112967)United States. National Institutes of Health (ES015339