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Tryptophan restriction blocks MYC-driven tumorigenesis and reprograms cancer cells to rely on lipolysis

ABSTRACT: Cancer cells vary in their nutritional dependencies, thus characterization of nutrient demand of each tumor type is needed to uncover specific vulnerabilities. We demonstrate that MYC-driven liver tumors rely on increased tryptophan (Trp) uptake to grow. By following 13C-Trp in vivo-labeling, we found that Trp catabolism is reduced while its incorporation into proteins is increased in tumors. Trp deprivation prevents MYC-driven tumors from arising, as well as the growth of xenografted cells while minimally affecting normal cells. Trp starvation causes a reduction in the expression of growth-related and ribosome biogenesis genes while enhancing regulators of lipid metabolism, including PPAR, and enzymes involved in -oxidation and ketosis. Under Trp starvation, surviving cancer cells are reprogramed to utilize lipids; thus, providing a high-fat diet rescued the growth of tumors starved of Trp. We shows that Trp deprivation may be a powerful tool to treat liver tumors if dietary fat intake is low.

ORGANISM(S): Mus musculus

PROVIDER: GSE213377 | GEO | 2023/09/30

REPOSITORIES: GEO

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Project description:Extended periods of waking result in physiological impairments in humans, rats, and flies. Sleep homeostasis, the increase in sleep observed following sleep loss, is believed to counter the negative effects of prolonged waking by restoring vital biological processes that are degraded during sleep deprivation. Sleep homeostasis, as with other behaviors, is influenced by both genes and environment. We report here that during periods of starvation, flies remain spontaneously awake but, in contrast to sleep deprivation, do not accrue any of the negative consequences of prolonged waking. Specifically, the homeostatic response and learning impairments that are a characteristic of sleep loss are not observed following prolonged waking induced by starvation. To identify the genes responsible for the protective effects of starvation we conducted transcription profiling of sleep deprived flies that accrue sleep debt compared to starved siblings that do not. Genes involved in lipid metabolism were highly enriched in our dataset of 84 differentially regulated transcripts. Follow up genetic studies established that 6 genes involved in lipid metabolism strongly influence sleep homeostasis. Two of these genes, brummer (bmm) and Lipid storage droplet 2 (Lsd2), are in the same lipolysis pathway but exert antagonistic effects on lipid storage. bmm mutant flies have excess fat stores and display a large homeostatic response following sleep deprivation. In contrast, Lsd2 mutant flies, which phenocopy aspects of starvation as measured by low triglyceride stores, do not exhibit a homeostatic response following sleep loss. Importantly, Lsd2 mutant flies are not learning impaired after sleep deprivation. These results provide the first genetic evidence, to our knowledge, that lipid metabolism plays an important role in regulating the homeostatic response and can protect against neuronal impairments induced by prolonged waking. Two-condition experiments: sleep deprived vs starved. RNA from 8 biological replicates for each condition was pooled in groups of 2 to create 4 samples. Each of the 4 samples is run in duplicate with untreated circadian matched controls.

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Tryptophan restriction blocks MYC-driven tumorigenesis and reprograms cancer cells to rely on lipolysis

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