Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer
Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2022
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/154360 |
| _version_ | 1826121702371753984 |
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| author | Loo, Ser Yue Toh, Li Ping Xie, William Haowei Pathak, Elina Tan, Wilson Ma, Siming Lee, May Yin Shatishwaran, S. Yeo, Joanna Zhen Zhen Yuan, Ju Ho, Yin Ying Peh, Esther Kai Lay Muniandy, Magendran Torta, Federico Chan, Jack Tan, Tira J. Sim, Yirong Tan, Veronique Tan, Benita Madhukumar, Preetha Yong, Wei Sean Ong, Kong Wee Wong, Chow Yin Tan, Puay Hoon Yap, Yoon Sim Deng, Lih-Wen Dent, Rebecca Foo, Roger Wenk, Markus R. Lee, Soo Chin Ho, Ying Swan Lim, Elaine Hsuen Tam, Wai Leong |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Loo, Ser Yue Toh, Li Ping Xie, William Haowei Pathak, Elina Tan, Wilson Ma, Siming Lee, May Yin Shatishwaran, S. Yeo, Joanna Zhen Zhen Yuan, Ju Ho, Yin Ying Peh, Esther Kai Lay Muniandy, Magendran Torta, Federico Chan, Jack Tan, Tira J. Sim, Yirong Tan, Veronique Tan, Benita Madhukumar, Preetha Yong, Wei Sean Ong, Kong Wee Wong, Chow Yin Tan, Puay Hoon Yap, Yoon Sim Deng, Lih-Wen Dent, Rebecca Foo, Roger Wenk, Markus R. Lee, Soo Chin Ho, Ying Swan Lim, Elaine Hsuen Tam, Wai Leong |
| author_sort | Loo, Ser Yue |
| collection | NTU |
| description | Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for β-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states. |
| first_indexed | 2024-10-01T05:36:50Z |
| format | Journal Article |
| id | ntu-10356/154360 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:36:50Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1543602023-02-28T17:11:30Z Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer Loo, Ser Yue Toh, Li Ping Xie, William Haowei Pathak, Elina Tan, Wilson Ma, Siming Lee, May Yin Shatishwaran, S. Yeo, Joanna Zhen Zhen Yuan, Ju Ho, Yin Ying Peh, Esther Kai Lay Muniandy, Magendran Torta, Federico Chan, Jack Tan, Tira J. Sim, Yirong Tan, Veronique Tan, Benita Madhukumar, Preetha Yong, Wei Sean Ong, Kong Wee Wong, Chow Yin Tan, Puay Hoon Yap, Yoon Sim Deng, Lih-Wen Dent, Rebecca Foo, Roger Wenk, Markus R. Lee, Soo Chin Ho, Ying Swan Lim, Elaine Hsuen Tam, Wai Leong School of Biological Sciences Genome Institute of Singapore, A*STAR National University of Singapore Science::Biological sciences Epithelial-Mesenchymal Transition Retinoic Acid Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for β-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) National Medical Research Council (NMRC) National Research Foundation (NRF) National University of Singapore (NUS), Temasek Laboratories Published version This research is supported by the National Medical Research Council, Singapore (OFIRG17may061, OFIRG19nov-0106, OFYIRG18May-0025, and CTGIIT18may0012); National Research Foundation Singapore (NRF-NRFF2015-04, NRFCRP22-2019-0003, NRF-CRP23-2019-0004, and NRFSBP-P4); National Cancer Institute Singapore Yong Siew Yoon Research Grant; Agency for Science, Technology and Research, Singapore (IAF-ICP I1901E0040); National University of Singapore via the Life Sciences Institute (LSI); and the Singapore Ministry of Education under its Research Centers of Excellence initiative. 2022-05-25T01:55:10Z 2022-05-25T01:55:10Z 2021 Journal Article Loo, S. Y., Toh, L. P., Xie, W. H., Pathak, E., Tan, W., Ma, S., Lee, M. Y., Shatishwaran, S., Yeo, J. Z. Z., Yuan, J., Ho, Y. Y., Peh, E. K. L., Muniandy, M., Torta, F., Chan, J., Tan, T. J., Sim, Y., Tan, V., Tan, B., ...Tam, W. L. (2021). Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer. Science Advances, 7(41), eabh2443-. https://dx.doi.org/10.1126/sciadv.abh2443 2375-2548 https://hdl.handle.net/10356/154360 10.1126/sciadv.abh2443 34613780 2-s2.0-85116908394 41 7 eabh2443 en OFIRG17may061 OFIRG19nov-0106 OFYIRG18May-0025 CTGIIT18may0012 NRF-NRFF2015-04 NRFCRP22-2019-0003 NRF-CRP23-2019-0004 NRFSBP-P4 IAF-ICP I1901E0040 Science Advances © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S.Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). application/pdf |
| spellingShingle | Science::Biological sciences Epithelial-Mesenchymal Transition Retinoic Acid Loo, Ser Yue Toh, Li Ping Xie, William Haowei Pathak, Elina Tan, Wilson Ma, Siming Lee, May Yin Shatishwaran, S. Yeo, Joanna Zhen Zhen Yuan, Ju Ho, Yin Ying Peh, Esther Kai Lay Muniandy, Magendran Torta, Federico Chan, Jack Tan, Tira J. Sim, Yirong Tan, Veronique Tan, Benita Madhukumar, Preetha Yong, Wei Sean Ong, Kong Wee Wong, Chow Yin Tan, Puay Hoon Yap, Yoon Sim Deng, Lih-Wen Dent, Rebecca Foo, Roger Wenk, Markus R. Lee, Soo Chin Ho, Ying Swan Lim, Elaine Hsuen Tam, Wai Leong Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer |
| title | Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer |
| title_full | Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer |
| title_fullStr | Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer |
| title_full_unstemmed | Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer |
| title_short | Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer |
| title_sort | fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer |
| topic | Science::Biological sciences Epithelial-Mesenchymal Transition Retinoic Acid |
| url | https://hdl.handle.net/10356/154360 |
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