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

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. Overall design: MYC-driven liver tumor model was generated by crossing TRE-MYC with LAP-tTA mouse. Male breeders with 2 copies of LAP-tTA and single copy of TRE-MYC was crossed with WT FVB females to generate LAP-tTA/TRE-MYC mice used for experiments. The breeders were maintained on doxycycline water (1 mg/mL). The females with the litters were transferred to a fresh cage on the day of birth to activate MYC overexpression. Animals were maintained on a regular chow diet. For comparison between WT and MYC overexpression, FVB WT males were used. Both the WT males and MYC overexpression males were 45 days old. For the experiments with different Trp diet, the mice were transferred to either the control diet, Low-Trp diet or No-Trp diet at the time points indicated