Wang, Z., Yip, L.Y., Lee, J.H.J. et al. Methionine is a metabolic dependency of tumor-initiating cells. Nat Med 25, 825–837 (2019). https://doi.org/10.1038/s41591-019-0423-5
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.
We thank SingHealth Advanced Molecular Pathology Laboratory for their assistance in generating tumor microarray data, Massimo Nichane, Kok Hao Edwin Lim, Lianghe Chen, Swea Ling Khaw, Monireh Soroush Noghabi, Rani Ettikan for technical assistance and Shyh-Chang Ng for critical comments. This research is support by the National Medical Research Council, Singapore (NMRC/TCR/007-NCC/2013), Agency for Science, Research and Technology, Singapore (1331AEG071; 334I00053; SPF 2012/001), and National Research Foundation, Singapore (NRF-NRFF2015-04).