Methionine is a metabolic dependency of tumor-initiating cells
Methionine is a metabolic dependency of tumor-initiating cells
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DOI：
10.1038/s41591-019-0423-5
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发表时间：
2019-05-01
期刊：
影响因子：
82.9
通讯作者：
Tam, Wai Leong
中科院分区：
文献类型：
--
作者：
Wang, Zhenxun;Yip, Lian Yee;Tam, Wai Leong
了解细胞代谢对于开发靶向癌症代谢途径的新型疗法具有巨大潜力。与正常组织相比，大块肿瘤细胞中的代谢途径发生了改变。然而，肿瘤内的癌细胞是异质性的，并且肿瘤起始细胞（TIC）是重要的治疗靶点，其在代谢上仍然未被表征。为了了解它们的代谢改变，我们进行了代谢组学和代谢物追踪分析，结果显示TIC具有由MAT 2A驱动的高度升高的甲硫氨酸循环活性和转甲基化速率。高甲硫氨酸循环活性导致甲硫氨酸消耗远远超过其再生，导致对外源性甲硫氨酸成瘾。对甲硫氨酸循环的药理学抑制，即使是短暂的，也足以削弱这些细胞的肿瘤起始能力。甲硫氨酸循环通量特异性地影响癌细胞的表观遗传状态并驱动肿瘤起始。甲硫氨酸循环酶也在其他肿瘤类型中富集，并且MAT 2A表达影响某些癌细胞对治疗抑制的敏感性。
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.