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Tumour fatty acid metabolism in the context of therapy resistance and obesity

Abstract

Fatty acid metabolism is known to support tumorigenesis and disease progression as well as treatment resistance through enhanced lipid synthesis, storage and catabolism. More recently, the role of membrane fatty acid composition, for example, ratios of saturated, monounsaturated and polyunsaturated fatty acids, in promoting cell survival while limiting lipotoxicity and ferroptosis has been increasingly appreciated. Alongside these insights, it has become clear that tumour cells exhibit plasticity with respect to fatty acid metabolism, responding to extratumoural and systemic metabolic signals, such as obesity and cancer therapeutics, to promote the development of aggressive, treatment-resistant disease. Here, we describe cellular fatty acid metabolic changes that are connected to therapy resistance and contextualize obesity-associated changes in host fatty acid metabolism that likely influence the local tumour microenvironment to further modify cancer cell behaviour while simultaneously creating potential new vulnerabilities.

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Fig. 1: The tumour lipidome and fatty acid metabolism pathways.
Fig. 2: Common features of therapy-resistant cells.
Fig. 3: The obese macroenvironment and microenvironment and their influence on cancer fatty acid metabolism and cancer behaviour.

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Acknowledgements

The authors apologise to colleagues whose work they were unable to discuss due to space constraints. Research in the Hoy lab related to the subject of this review is supported by a Robinson Fellowship and funding from the University of Sydney and Sydney Catalyst. L.M.B. is supported by a Principal Cancer Research Fellowship produced with the financial and other support of Cancer Council SA’s Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health, and the US Department of Defense. The Hoy and Butler labs are supported by a Movember Revolutionary Team Award from the Movember Foundation and the Prostate Cancer Foundation of Australia (MRTA3).

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A.J.H., S.R.N. and L.M.B. researched and discussed the relevant research literature, wrote the manuscript, and drafted the figures.

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Glossary

Tumour lipidome

The full lipid complement of the tumour that captures the levels of lipid classes and species.

Macropinocytosis

An endocytic process that involves the engulfment of extracellular content, including soluble molecules, nutrients and antigens, in vesicles known as macropinosomes.

Type 2 diabetes

A progressive metabolic condition in which the body becomes resistant to the normal effects of insulin and/or gradually loses the capacity to produce enough insulin in the pancreas.

Metabolic syndrome

A cluster of conditions, including abdominal obesity, high blood pressure, high blood glucose, high serum triglycerides and low serum high-density lipoprotein, that occur together and increase the risk of heart disease, stroke and type 2 diabetes.

Lipophagy

The autophagic degradation of intracellular lipid droplets.

Resveratrol

A phenolic compound of the stilbene family present in wines and various parts of the grape that exhibits antioxidant and antiproliferative activities.

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Hoy, A.J., Nagarajan, S.R. & Butler, L.M. Tumour fatty acid metabolism in the context of therapy resistance and obesity. Nat Rev Cancer (2021). https://doi.org/10.1038/s41568-021-00388-4

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