Tumor-Initiating Cells Are Reliant on Methionine to Promote Cancer

Tumor-initiating cells (TIC) are often resistant to chemotherapy and are responsible for increased cancer aggressiveness and relapse. Although TICs and non-TIC cells exhibit distinct metabolic profiles, there is currently no clear understanding of cellular metabolic differences between TICs and bulk tumor cells. To ascertain which metabolites are critical for TICs, Wang, Yip, and colleagues performed global metabolomics analyses and identified an enrichment of methionine-cycle metabolites in patient-derived CD166⁺ lung TICs compared with matched adherent non-TIC lung cancer cells. In particular, TICs exhibited increased levels of methionine-cycle metabolites such as methionine, S-adenosyl methionine (SAM), and S-adenosyl homocysteine (SAH). Consistent with these findings, key enzymes in the methionine cycle, such as methionine adenosyltransferase II alpha (MAT2A) and methylenetetrahydrofolate reductase, were found to be overexpressed in human lung tumors compared with normal lung specimens. Of interest, TICs also exhibited increased histone methylation marks. Transient starvation of methionine, but not other essential amino acids, abolished the tumorigenic potential of lung TICs without a general loss of cell viability; further, rescue of methionine-starved cells through supplementation with exogenous methionine, but not homocysteine, successfully restored histone methylation. High SAM consumption rates by TICs were determined to drive the reliance of TICs on exogenous methionine to methylate histones, and treatment of TICs with an MAT2A inhibitor, but not cisplatin, significantly reduced intracellular levels of SAM and SAH, histone methylation, and tumor growth. Taken together, these results show that TICs are dependent upon exogenous methionine to drive the methionine cycle, global histone methylation, and increased tumorigenicity; thus, transient methionine starvation and pharmacologic inhibition of the methionine cycle are potential TIC-targeting strategies.

Wang Z, Yip LY, Lee JHJ, Wu Z, Chew HY, Chong PKW, et al. Methionine is a metabolic dependency of tumor-initiating cells. Nat Med 2019;25:825–37.

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