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Metabolic determinants of tumour initiation

Abstract

Tumours exhibit notable metabolic alterations compared with their corresponding normal tissue counterparts. These metabolic alterations can support anabolic growth, enable survival in hostile environments and regulate gene expression programmes that promote malignant progression. Whether these metabolic changes are selected for during malignant transformation or can themselves be drivers of tumour initiation is unclear. However, intriguingly, many of the major bottlenecks for tumour initiation — control of cell fate, survival and proliferation — are all amenable to metabolic regulation. In this article, we review evidence demonstrating a critical role for metabolic pathways in processes that support the earliest stages of tumour development. We discuss how cell-intrinsic factors, such as the cell of origin or transforming oncogene, and cell-extrinsic factors, such as local nutrient availability, promote or restrain tumour initiation. Deeper insight into how metabolic pathways control tumour initiation will improve our ability to design metabolic interventions to limit tumour incidence.

Key points

  • Metabolism is linked to key processes that are required for tumour initiation: cell fate control, survival, biomass accumulation and proliferation.

  • Through their role as co-substrates for chromatin-modifying enzymes, metabolites have the potential to influence cell fate programmes that control tumour initiation.

  • Hereditary cancer syndromes highlight how mutations in metabolic enzymes can predispose to cancer through the accumulation of the oncometabolites succinate, fumarate and 2-hydroxyglutarate.

  • The intrinsic metabolic configurations of tissues or cells might facilitate or antagonize oncogenic transformation.

  • Environmental factors, including diet, inflammation, hypoxia and nutrient availability, interact to control many processes related to tumour initiation and progression.

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Fig. 1: Challenges in tumour initiation.
Fig. 2: Metabolites have the potential to regulate chromatin-modifying enzymes.
Fig. 3: ROS control processes related to tumour evolution.
Fig. 4: Metabolic pathways support biomass accumulation.
Fig. 5: Metabolic regulation of hypoxic responses.
Fig. 6: Environmental factors influencing tumour initiation.

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Acknowledgements

The authors thank S. Baksh (Sloan Kettering Institute, USA) for critical reading of the manuscript and members of the Finley laboratory for helpful discussion. L.W.S.F. is a Searle Scholar. The authors acknowledge the support of a Human Frontier Science Program Fellowship LT000200/2021-L (to J.S.B.), grants to L.W.S.F. from the Pershing Square Sohn Prize for Cancer Research and the NIH/NCI (R37CA252305), and the Memorial Sloan Kettering Cancer Center Support Grant P30CA008748.

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J.S.B. and L.W.S.F. contributed equally to all aspects of the article.

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Correspondence to Lydia W. S. Finley.

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Nature Reviews Endocrinology thanks Christian Frezza and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

α-ketoglutarate-dependent dioxygenases

A family of iron-containing enzymes that use molecular oxygen and α-ketoglutarate to oxidize a substrate, producing succinate and carbon dioxide as by-products.

Anaplerosis

Influx of intermediates into the tricarboxylic acid cycle.

Autophagy

The process by which cellular components are delivered to the lysosome for digestion.

Cataplerosis

Efflux of intermediates from the tricarboxylic acid cycle to other metabolic pathways.

Conditional essentiality

While essential genes are broadly considered to be required for cell viability under a wide array of conditions, genes exhibiting conditional essentiality are required for cell viability under specific circumstances, such as loss of another gene, activation of a signalling pathway or restriction of extracellular nutrients.

Epithelial–mesenchymal transition

A process in which epithelial cells change fate towards mesenchymal lineages, thereby gaining migratory capacity, invasiveness and often stem-like features.

Homeostatic stem cells

Undifferentiated progenitor cells that maintain tissue integrity by balancing self-renewal and differentiation into mature cells.

Isotope-tracing studies

Experiments in which heavy-labelled atoms are followed through metabolic networks, often by incubating cells with labelled forms of nutrients, such as glucose or glutamine, and then assessing labelling of downstream metabolic intermediates.

Jumonji-domain-containing histone demethylases

Members of the family of α-ketoglutarate-dependent dioxygenases that contain a common structural domain that facilitates protein demethylation.

Macropinocytosis

A non-selective form of endocytosis in which cells engulf extracellular fluid and other macromolecular cargo.

Myeloid cells

Bone-marrow-derived cells of a common lineage, including monocytes, macrophages, dendritic cells and granulocytes.

Receptor-mediated endocytosis

A process by which cell surface receptors and their ligands are internalized in a clathrin-dependent fashion.

Stromal cells

Cells that functionally or architecturally support tissues throughout the body.

Tumour initiation

The process in which a cell (‘cell of origin’) acquires the ability to self-renew, propagate and withstand elimination to eventually give rise to a tumour.

Tumour microenvironment

(TME). The cells and molecules that comprise the local ecosystem of a tumour, including the cancer cells, stromal and immune cells and blood vessels, as well as the interstitial fluid and any proteins, metabolites or other molecules therein.

Tumour progression

The evolution of a tumour towards increased malignancy; can refer to increases in tumour size, stage or dissemination to new sites for metastatic growth.

Tumour-associated stem cells

A subset of cancer cells within a tumour that display capacity for self-renewal and differentiation; these cells are often associated with therapy resistance and tumour aggressiveness.

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Brunner, J.S., Finley, L.W.S. Metabolic determinants of tumour initiation. Nat Rev Endocrinol (2022). https://doi.org/10.1038/s41574-022-00773-5

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