Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition

Yoav D. Shaul; Elizaveta Freinkman; William C. Comb; Jason R. Cantor; Wai Leong Tam; Prathapan Thiru; Dohoon Kim; Naama Kanarek; Michael E. Pacold; Walter W. Chen; Brian Bierie; Richard Possemato; Ferenc Reinhardt; Robert A. Weinberg; Michael B. Yaffe; David M. Sabatini

doi:10.1016/j.cell.2014.07.032

Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition

Yoav D. Shaul, Elizaveta Freinkman, William C. Comb, Jason R. Cantor, Wai Leong Tam, Prathapan Thiru, Dohoon Kim, Naama Kanarek, Michael E. Pacold, Walter W. Chen, Brian Bierie, Richard Possemato, Ferenc Reinhardt, Robert A. Weinberg, Michael B. Yaffe, David M. Sabatini^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

169 Scopus citations

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.

Original language	English
Pages (from-to)	1094-1109
Number of pages	16
Journal	Cell
Volume	158
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2014.07.032
State	Published - 28 Aug 2014
Externally published	Yes

Bibliographical note

Funding Information:
We thank all members of the Sabatini Lab for helpful suggestions and Tom DiCesare for graphical assistance. This work was supported by grants from the NIH (RO1 CA103866 and AI047389 to D.M.S.; K99 CA168940 to R.P.), the Life Science Research Foundation and Ludwig Postdoctoral Fellowship (to Y.D.S.), the American Cancer Society fellowship (PF-12-099-01-TGB) (to J.R.C.), the Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation (DRG112-12) (to M.E.P.), American Cancer Society-Ellison Foundation Postdoctoral Fellowship (PF-13-356-01-TBE) (to W.C.C.), the Ruth L. Kirchstein NRSA F30 fellowship (to W.W.C.), and the Hope Funds for Cancer Research Fellowship (HFCR-13-03-03) and Department of Defense Breast Cancer Research Program (BC123066) (to E.F.). M.B.Y. is supported by NIH grants (CA112967 and ES015339). D.M.S. is an investigator of the Howard Hughes Medical Institute.

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Shaul, Y. D., Freinkman, E., Comb, W. C., Cantor, J. R., Tam, W. L., Thiru, P., Kim, D., Kanarek, N., Pacold, M. E., Chen, W. W., Bierie, B., Possemato, R., Reinhardt, F., Weinberg, R. A., Yaffe, M. B., & Sabatini, D. M. (2014). Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition. Cell, 158(5), 1094-1109. https://doi.org/10.1016/j.cell.2014.07.032

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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.",

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note = "Funding Information: We thank all members of the Sabatini Lab for helpful suggestions and Tom DiCesare for graphical assistance. This work was supported by grants from the NIH (RO1 CA103866 and AI047389 to D.M.S.; K99 CA168940 to R.P.), the Life Science Research Foundation and Ludwig Postdoctoral Fellowship (to Y.D.S.), the American Cancer Society fellowship (PF-12-099-01-TGB) (to J.R.C.), the Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation (DRG112-12) (to M.E.P.), American Cancer Society-Ellison Foundation Postdoctoral Fellowship (PF-13-356-01-TBE) (to W.C.C.), the Ruth L. Kirchstein NRSA F30 fellowship (to W.W.C.), and the Hope Funds for Cancer Research Fellowship (HFCR-13-03-03) and Department of Defense Breast Cancer Research Program (BC123066) (to E.F.). M.B.Y. is supported by NIH grants (CA112967 and ES015339). D.M.S. is an investigator of the Howard Hughes Medical Institute. ",

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AU - Tam, Wai Leong

AU - Thiru, Prathapan

AU - Kim, Dohoon

AU - Kanarek, Naama

AU - Pacold, Michael E.

AU - Chen, Walter W.

AU - Bierie, Brian

AU - Possemato, Richard

AU - Reinhardt, Ferenc

AU - Weinberg, Robert A.

AU - Yaffe, Michael B.

AU - Sabatini, David M.

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N2 - 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.

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Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition

Abstract

Bibliographical note

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