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Title: Methionine is a metabolic dependency of tumor-initiating cells
Authors: Wang, Zhenxun
Yip, Lian Yee
Lee, Jane Jia Hui
Wu, Zhengwei
Chew, Hui Yi
Chong, William Pooi Kiat
Teo, Chin Chye
Ang, Heather Yin-Kuan
Peh, Esther Kai Lay
Yuan, Ju
Ma, Siming
Choo, Kimberly Li Shi
Basri, Nurhidayah
Jiang, Xia
Yu, Qiang
Hillmer, Axel M.
Lim, Wan Teck
Lim, Tony Kiat Hon
Takano, Angela
Tan, Eng Huat
Tan, Daniel Shao Weng
Ho, Ying Swan
Lim, Bing
Tam, Wai Leong
Keywords: Science::Biological sciences
Issue Date: 2019
Source: Wang, Z., Yip, L. Y., Lee, J. J. H., Wu, Z., Chew, H. Y., Chong, W. P. K., Teo, C. C., Ang, H. Y., Peh, E. K. L., Yuan, J., Ma, S., Choo, K. L. S., Basri, N., Jiang, X., Yu, Q., Hillmer, A. M., Lim, W. T., Lim, T. K. H., Takano, A., ...Tam, W. L. (2019). Methionine is a metabolic dependency of tumor-initiating cells. Nature Medicine, 25(5), 825-837.
Project: NRF-NRFF2015-04
NMRC/TCR/007- NCC/2013
SPF 2012/001
Journal: Nature Medicine
Abstract: Understanding cellular metabolism holds immense potential for developing new classes of therapeutics that target metabolic pathways in cancer. Metabolic pathways are altered in bulk neoplastic cells in comparison to normal tissues. However, carcinoma cells within tumors are heterogeneous, and tumor-initiating cells (TICs) are important therapeutic targets that have remained metabolically uncharacterized. To understand their metabolic alterations, we performed metabolomics and metabolite tracing analyses, which revealed that TICs have highly elevated methionine cycle activity and transmethylation rates that are driven by MAT2A. High methionine cycle activity causes methionine consumption to far outstrip its regeneration, leading to addiction to exogenous methionine. Pharmacological inhibition of the methionine cycle, even transiently, is sufficient to cripple the tumor-initiating capability of these cells. Methionine cycle flux specifically influences the epigenetic state of cancer cells and drives tumor initiation. Methionine cycle enzymes are also enriched in other tumor types, and MAT2A expression impinges upon the sensitivity of certain cancer cells to therapeutic inhibition.
ISSN: 1078-8956
DOI: 10.1038/s41591-019-0423-5
Rights: © 2019 The Author(s), under exclusive licence to Springer Nature America, Inc. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:SBS Journal Articles

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