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 hi...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2017
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| Online Access: | http://hdl.handle.net/1721.1/109548 https://orcid.org/0000-0003-3688-2378 https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0002-2401-0030 https://orcid.org/0000-0002-0895-3557 https://orcid.org/0000-0002-9547-3251 https://orcid.org/0000-0002-1446-7256 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering 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 |
| author_sort | Freinkman, Elizaveta |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T12:45:20Z |
| format | Article |
| id | mit-1721.1/109548 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:45:20Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1095482022-10-01T10:55:47Z Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition 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 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) Koch Institute for Integrative Cancer Research at MIT Shaul, Yoav Kim, Dohoon Pacold, Michael E Chen, Walter W. Possemato, Richard Reinhardt, Ferenc Weinberg, Robert A Yaffe, Michael B Sabatini, David 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) 2017-06-02T17:24:08Z 2017-06-02T17:24:08Z 2014-08 2014-06 Article http://purl.org/eprint/type/JournalArticle 0092-8674 1097-4172 http://hdl.handle.net/1721.1/109548 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 https://orcid.org/0000-0003-3688-2378 https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0002-2401-0030 https://orcid.org/0000-0002-0895-3557 https://orcid.org/0000-0002-9547-3251 https://orcid.org/0000-0002-1446-7256 en_US http://dx.doi.org/10.1016/j.cell.2014.07.032 Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | 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 Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition |
| title | Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition |
| title_full | Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition |
| title_fullStr | Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition |
| title_full_unstemmed | Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition |
| title_short | Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition |
| title_sort | dihydropyrimidine accumulation is required for the epithelial mesenchymal transition |
| url | http://hdl.handle.net/1721.1/109548 https://orcid.org/0000-0003-3688-2378 https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0002-2401-0030 https://orcid.org/0000-0002-0895-3557 https://orcid.org/0000-0002-9547-3251 https://orcid.org/0000-0002-1446-7256 |
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