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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:Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic high-fat diet was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In prostate cancer patients, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like tumor-associated macrophages. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the tumor microenvironment and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. Murine serum assays are reported in the current study MTBLS3316.Murine prostate assays are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS3317' rel='noopener noreferrer' target='_blank'>MTBLS3317</a>.

Project description:Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic high-fat diet was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In prostate cancer patients, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like tumor-associated macrophages. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the tumor microenvironment and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. Murine prostate assays are reported in the current study MTBLS3317.Murine serum assays are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS3316' rel='noopener noreferrer' target='_blank'>MTBLS3316</a>.

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

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