Journal
NATURE
Volume 599, Issue 7884, Pages 302-307Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-04049-2
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Funding
- Damon Runyon Cancer Research Foundation [DRG-2299-17, DRG-2241-15]
- NIH Pathway to Independence Award [K99CA234221]
- NIH [T32GM007287, U01CA210171, P50CA127003, R35CA242379, R01CA168653, R01CA201276, P30CA14051, UM1 CA186107, U01 CA176726, P01 CA87969, U01 CA167552, R03 CA223619]
- Lustgarten Foundation
- Dana-Farber Cancer Institute Hale Family Center for Pancreatic Cancer Research
- Stand Up To Cancer
- Pancreatic Cancer Action Network
- Noble Effort Fund
- Wexler Family Fund
- Bob Parsons Fund
- Emerald Foundation
- Howard Hughes Medical Institute
- MIT Center for Precision Cancer Medicine
- Ludwig Center at MIT
- Promises for Purple
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Dietary interventions can impact tumour growth by altering metabolite levels in the tumour microenvironment. While caloric restriction and a ketogenic diet have different effects on tumour growth inhibition, with caloric restriction affecting lipid levels and fatty acid balance, the ketogenic diet influences tumour fatty acid desaturation and composition.
Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth(1-5). Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumour progression by lowering blood glucose and insulin levels(6-8), we found that only CR inhibits the growth of select tumour allografts in mice, suggesting that other mechanisms contribute to tumour growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumours. Upregulation of stearoyl-CoA desaturase (SCD), which synthesises monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumour SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumour growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumour SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumours, and changing the KD fat composition to increase tumour saturated fatty acid levels cooperates with decreased tumour SCD activity to slow tumour growth. These data suggest that diet-induced mismatches between tumour fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumour growth. Lien et al. show that low glycemic diets can reduce tumour growth by deregulating lipid metabolism.
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