# Dietary methionine influences therapy in mouse cancer models and alters human metabolism

## Abstract

Nutrition exerts considerable effects on health, and dietary interventions are commonly used to treat diseases of metabolic aetiology. Although cancer has a substantial metabolic component1, the principles that define whether nutrition may be used to influence outcomes of cancer are unclear2. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. By contrast, whether specific dietary interventions can influence the metabolic pathways that are targeted in standard cancer therapies is not known. Here we show that dietary restriction of the essential amino acid methionine—the reduction of which has anti-ageing and anti-obesogenic properties—influences cancer outcome, through controlled and reproducible changes to one-carbon metabolism. This pathway metabolizes methionine and is the target of a variety of cancer interventions that involve chemotherapy and radiation. Methionine restriction produced therapeutic responses in two patient-derived xenograft models of chemotherapy-resistant RAS-driven colorectal cancer, and in a mouse model of autochthonous soft-tissue sarcoma driven by a G12D mutation in KRAS and knockout of p53 (KrasG12D/+;Trp53−/−) that is resistant to radiation. Metabolomics revealed that the therapeutic mechanisms operate via tumour-cell-autonomous effects on flux through one-carbon metabolism that affects redox and nucleotide metabolism—and thus interact with the antimetabolite or radiation intervention. In a controlled and tolerated feeding study in humans, methionine restriction resulted in effects on systemic metabolism that were similar to those obtained in mice. These findings provide evidence that a targeted dietary manipulation can specifically affect tumour-cell metabolism to mediate broad aspects of cancer outcome.

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### Extended Data Fig. 7 Dietary restriction of methionine sensitizes mouse models of RAS-driven autochthonous sarcoma to radiation.

a, Volcano plots of metabolites in tumour, plasma and liver, and pathway analysis of metabolites significantly changed (*P < 0.05, two-tailed Student’s t-test) by dietary restriction of methionine alone (false discovery rate < 1). b, Spearman’s rank correlation coefficients of fold change of metabolites in tumour, plasma and liver induced by methionine restriction. c, Volcano plots of metabolites in tumour, plasma and liver, and pathway analysis of metabolites significantly changed (*P < 0.05, two-tailed Student’s t-test) by dietary restriction of methionine and radiation (false discovery rate < 0.5). d, Spearman’s rank correlation coefficients of fold change of metabolites in tumour, plasma and liver induced by methionine restriction and radiation. e, Relative intensity of metabolites related to cysteine and methionine metabolism, and energy balance in tumours. Mean ± s.d. n = 7 mice per group, except for the methionine-restriction group (n = 6). *P < 0.05 versus control, by two-tailed Student’s t-test. f, g, The largest effects on metabolism occurred in the combination of diet and radiation. f, Effect of methionine restriction and radiation alone, or in combination, on metabolites in tumour, plasma and liver, evaluated by taking the log10 of fold change. Box limits are the 25th and 75th percentiles, centre line is the median, and the whiskers are the minimal and maximal values. The data represent metabolites in liver (319), plasma (308) and tumour (332) from n = 7 mice per group, except for the methionine-restriction group (n = 6). g, Numbers of metabolites significantly changed (*P < 0.05, two-tailed Student’s t-test) by methionine restriction and radiation alone, or in combination. Source data

### Extended Data Fig. 8 Dietary restriction of methionine can be achieved in humans.

a, Heat map of significantly changed (*P < 0.05, two-tailed Student’s t-test) plasma metabolites by dietary intervention, in six human subjects. b, Volcano plot of plasma metabolites. P values were determined by two-tailed Student’s t-test. c, Pathway analysis of altered (*P < 0.05, two-tailed Student’s t-test) plasma metabolites. d, Relative intensity of amino acids in plasma. n = 6 biologically independent humans. *P < 0.05 by two-tailed Student’s t-test. Source data

### Extended Data Fig. 9 Comparative metabolic effects of methionine restriction across mouse models and humans.

a, Spearman’s rank correlation coefficients of fold changes of methionine-related metabolites induced by methionine restriction (defined in Extended Data Fig. 3f) in plasma samples from non-tumour bearing C57BL/6J mice, CRC119 and CRC240 mouse models, the sarcoma mouse model and healthy human subjects. b, Spearman’s rank correlation coefficients among different models in a, ranked from the highest to the lowest. Source data

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• #### DOI

https://doi.org/10.1038/s41586-019-1437-3