Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition.
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Abstract | 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. |
Year of Publication | 2014
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Journal | Cell
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Volume | 158
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Issue | 5
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Pages | 1094-109
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Date Published | 2014 Aug 28
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ISSN | 1097-4172
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DOI | 10.1016/j.cell.2014.07.032
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PubMed ID | 25171410
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PubMed Central ID | PMC4250222
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Grant list | R01 AI047389 / AI / NIAID NIH HHS / United States
R01 CA103866 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
R01 ES015339 / ES / NIEHS NIH HHS / United States
K99 CA168940 / CA / NCI NIH HHS / United States
AI047389 / AI / NIAID NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States
R37 AI047389 / AI / NIAID NIH HHS / United States
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