Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition
Author(s)Freinkman, Elizaveta; Comb, William C.; Cantor, Jason R.; Tam, Wai Leong; Thiru, Prathapan; Kanarek, Naama; Bierie, Brian; Shaul, Yoav; Kim, Dohoon; Chen, Walter W.; Possemato, Richard; Reinhardt, Ferenc; Weinberg, Robert A; Yaffe, Michael B; Sabatini, David; Pacold, Michael Edward; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research; Ludwig Center for Molecular Oncology (Massachusetts Institute of Technology)
Shaul, Yoav D.; Freinkman, Elizaveta; Comb, William C.; Cantor, Jason R.; Tam, Wai Leong; Thiru, Prathapan; Kim, Dohoon et al. “Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition.” Cell 158, no. 5 (August 2014): 1094–1109 © 2014 Elsevier Inc
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