Diet is a key health determinant. Its impact on diabetes and cardiovascular disease is well known. But does it matter for cancer outcome?
Recent discoveries suggest so. Omitting selected amino acids (components of protein) from the diet can slow tumor growth in mice. Fasting enhances the sensitivity of some tumors to chemotherapy. A ketogenic diet does too because the carbohydrate level is so low that eating fails to induce insulin. Insulin is the key hormonal indicator of the “fed” state and a factor in tumor growth.
Diet also impacts anticancer immune response. In ways not yet well understood, the bacteria in our intestine (the gut microbiome), which are impacted by the food that we eat, shape the activity of tumor-attacking T cells. A high-fiber diet promotes, via the microbiome, immunotherapy efficacy.
At the Ludwig Princeton Branch, we will explore the biochemical basis by which diet impacts cancer. We will build rational and quantitative understanding of diet’s influence on cancer’s growth, chemotherapy sensitivity, and immune response, and how these factors vary across tumor types and individuals. In so doing, we will lay the foundation for designer diets that robustly suppress cancer. In parallel, we will engage clinicians to prove the benefits of tailored diets for cancer patients.
Related Publications
Mann CG, MacArthur MR, Zhang J, Gong S, AbuSalim JE, Hunter CJ, Lu W, Agius T, Longchamp A, Allagnat F, Rabinowitz J, Mitchell JR, De Bock K, Mitchell SJ. Sulfur Amino Acid Restriction Enhances Exercise Capacity in Mice by Boosting Fat Oxidation in Muscle. bioRxiv [Preprint]. 2024 Jul 1:2024.06.27.601041. doi: 10.1101/2024.06.27.601041. PMID: 39005372; PMCID: PMC11244859.
Dietary restriction of the sulfur-containing amino acids methionine and cysteine (SAAR) improves body composition, enhances insulin sensitivity, and extends lifespan; benefits seen also with endurance exercise. Yet, the impact of SAAR on skeletal muscle remains largely unexplored. Here we demonstrate that one week of SAAR in sedentary, young, male mice increases endurance exercise capacity. Indirect calorimetry showed that SAAR increased lipid oxidation at rest and delayed the onset of carbohydrate utilization during exercise. Transcriptomic analysis revealed increased expression of genes involved in fatty acid catabolism especially in glycolytic muscle following SAAR. These findings were functionally supported by increased fatty acid circulatory turnover flux and muscle β-oxidation. Reducing lipid uptake from circulation through endothelial cell (EC)-specific CD36 deletion attenuated the running phenotype. Mechanistically, VEGF-signaling inhibition prevented exercise increases following SAAR, without affecting angiogenesis, implicating noncanonical VEGF signaling and EC CD36-dependent fatty acid transport in regulating exercise capacity by influencing muscle substrate availability.
Ferrer M, Mourikis N, Davidson E, O Kleeman S, Zaccaria M, Habel J, Rubino R, Gao Q, Flint TR, Young L, Connell CM, Lukey MJ, Goncalves MD, White EP, Venkitaraman AR, Janowitz T. Cell Metab. 2023 Jul 11;35(7):1147-1162.e7. doi: 10.1016/j.cmet.2023.05.008. PMID: 37311455
Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrate ketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepatic ketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associated murine models of cancer cachexia, we describe delayed tumor growth but accelerated cachexia onset and shortened survival in mice fed KD. Mechanistically, this uncoupling is a consequence of the biochemical interaction of two NADPH-dependent pathways. Within the tumor, increased lipid peroxidation and, consequently, saturation of the glutathione (GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impair corticosterone biosynthesis.
TeSlaa T, Ralser M, Fan J, Rabinowitz, J. D. (2023) Nat Metab., 2023 Aug 5(8):1275-1289. doi; 10.1038/s42255-023-00863-2 PMID: 37612403
The pentose phosphate pathway (PPP) is a glucose-oxidizing pathway that runs in parallel to upper glycolysis to produce ribose 5-phosphate and nicotinamide adenine dinucleotide phosphate (NADPH). Ribose 5-phosphate is used for nucleotide synthesis, while NADPH is involved in redox homoeostasis as well as in promoting biosynthetic processes, such as the synthesis of tetrahydrofolate, deoxyribonucleotides, proline, fatty acids and cholesterol. Through NADPH, the PPP plays a critical role in suppressing oxidative stress, including in certain cancers, in which PPP inhibition may be therapeutically useful.