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The metabolism of cancer cells during metastasis

Abstract

Metastasis formation is the major cause of death in most patients with cancer. Despite extensive research, targeting metastatic seeding and colonization is still an unresolved challenge. Only recently, attention has been drawn to the fact that metastasizing cancer cells selectively and dynamically adapt their metabolism at every step during the metastatic cascade. Moreover, many metastases display different metabolic traits compared with the tumours from which they originate, enabling survival and growth in the new environment. Consequently, the stage-dependent metabolic traits may provide therapeutic windows for preventing or reducing metastasis, and targeting the new metabolic traits arising in established metastases may allow their eradication.

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Fig. 1: Metabolite plasticity and flexibility in metastasizing cancer cells.
Fig. 2: The metabolism of invading and circulating (detached) cancer cells.
Fig. 3: The metabolism of cancer cells colonizing in distant organs.
Fig. 4: Nutrient inflexibility during metastasis formation.
Fig. 5: Selection and adaptation processes contributing to the metabolic differences between primary tumours and metastases.

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Acknowledgements

The authors regret the inability to cite all studies that have shaped the understanding of cancer metastasis metabolism. S.-M.F. acknowledges funding from the European Research Council under the ERC Consolidator Grant Agreement n. 771486 — MetaRegulation, FWO — Odysseus II, FWO research projects (G098120N, G088318N), KU Leuven — Methusalem Co-Funding and Fonds Baillet Latour. G.B. acknowledges funding from the Flemish cancer society Stichting tegen Kanker (STK 1303), the Flemish government FWO (G0A0818N) and the National Institutes of Health (NIH)/National Cancer Institute (NCI) (R01CA201537).

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Both authors contributed equally to all aspects of the article.

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Correspondence to Gabriele Bergers or Sarah-Maria Fendt.

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S.-M.F. has received funding from Bayer, Merck and BlackBelt Therapeutics and has consulted for Fund+. G.B. declares no competing interests.

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Nature Reviews Cancer thanks S.A. Benitah, S.J. Morrison and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Metastatic virulence genes

Genes or factors that confer proliferation and/or survival advantages to metastasizing cancer cells at the secondary site without affecting primary tumours.

Metabolic plasticity

A metabolite can be used for multiple purposes.

Metabolic flexibility

Several metabolites can be used for the same purpose.

Divergence in metabolism

Divergent properties appear in distinct molecular subsets of cancer and contribute to metabolic heterogeneity.

Anaplerosis

Refilling of the tricarboxylic acid (TCA) cycle with carbon.

Glutaminolysis

Full oxidation of glutamine.

Peroxidation

A chemical reaction between mainly unsaturated fatty acids and the reactive forms of oxygen.

Nutrient inflexibility

A dependence on one nutrient despite the fact that multiple nutrients can lead to the production of a certain metabolite.

Reductive carboxylation

A metabolic pathway in which α-ketoglutarate is converted to citrate through a reaction with carbon dioxide.

Glucose fermentation

A biological process in which glucose is converted to lactate.

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Bergers, G., Fendt, SM. The metabolism of cancer cells during metastasis. Nat Rev Cancer 21, 162–180 (2021). https://doi.org/10.1038/s41568-020-00320-2

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