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

Publication ,  Journal Article
Gao, X; Sanderson, SM; Dai, Z; Reid, MA; Cooper, DE; Lu, M; Richie, JP; Ciccarella, A; Calcagnotto, A; Mikhael, PG; Mentch, SJ; Liu, J ...
Published in: Nature
August 2019

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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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

August 2019

Volume

572

Issue

7769

Start / End Page

397 / 401

Location

England

Related Subject Headings

  • Treatment Outcome
  • Sulfur
  • Soft Tissue Neoplasms
  • Sarcoma
  • Proof of Concept Study
  • Mutation
  • Middle Aged
  • Mice
  • Methionine
  • Metabolomics
 

Citation

APA
Chicago
ICMJE
MLA
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Gao, X., Sanderson, S. M., Dai, Z., Reid, M. A., Cooper, D. E., Lu, M., … Locasale, J. W. (2019). Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature, 572(7769), 397–401. https://doi.org/10.1038/s41586-019-1437-3
Gao, Xia, Sydney M. Sanderson, Ziwei Dai, Michael A. Reid, Daniel E. Cooper, Min Lu, John P. Richie, et al. “Dietary methionine influences therapy in mouse cancer models and alters human metabolism.Nature 572, no. 7769 (August 2019): 397–401. https://doi.org/10.1038/s41586-019-1437-3.
Gao X, Sanderson SM, Dai Z, Reid MA, Cooper DE, Lu M, et al. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature. 2019 Aug;572(7769):397–401.
Gao, Xia, et al. “Dietary methionine influences therapy in mouse cancer models and alters human metabolism.Nature, vol. 572, no. 7769, Aug. 2019, pp. 397–401. Pubmed, doi:10.1038/s41586-019-1437-3.
Gao X, Sanderson SM, Dai Z, Reid MA, Cooper DE, Lu M, Richie JP, Ciccarella A, Calcagnotto A, Mikhael PG, Mentch SJ, Liu J, Ables G, Kirsch DG, Hsu DS, Nichenametla SN, Locasale JW. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature. 2019 Aug;572(7769):397–401.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

August 2019

Volume

572

Issue

7769

Start / End Page

397 / 401

Location

England

Related Subject Headings

  • Treatment Outcome
  • Sulfur
  • Soft Tissue Neoplasms
  • Sarcoma
  • Proof of Concept Study
  • Mutation
  • Middle Aged
  • Mice
  • Methionine
  • Metabolomics