title: Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Yoav D
authors.initials: YD
authors.lastname: Shaul
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Freinkman
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Comb
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Cantor
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA; Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Wai Leong
authors.initials: WL
authors.lastname: Tam
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Prathapan
authors.initials: P
authors.lastname: Thiru
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Dohoon
authors.initials: D
authors.lastname: Kim
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Naama
authors.initials: N
authors.lastname: Kanarek
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA; Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Pacold
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Walter W
authors.initials: WW
authors.lastname: Chen
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Bierie
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Possemato
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Reinhardt
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIT Ludwig Center for Molecular Oncology, Cambridge, MA 02139, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yaffe
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address: sabatini@wi.mit.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D011743:Pyrimidines / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D011743:Pyrimidines; D034741:RNA, Small Interfering; D042943:Dihydrouracil Dehydrogenase (NADP); C030986:pyrimidine