In the 1920s, Otto Warburg identified the first molecular feature of cancer: altered metabolism in the form of increased fermentation of glucose to lactate. This glucose-avidity of cancer underlies its modern diagnosis using FDG-PET imaging. Subsequent research identified enhanced nucleotide synthesis as another defining feature of cancer, leading to the development of the first class of targeted chemotherapeutics, antifolates. One of these, pemetrexed, discovered at Princeton by late Professor Edward Taylor, remains a first line therapy for lung cancer.
Building on the successes, the Ludwig Princeton Branch will investigate the fundamentals of metabolism, and how these go awry in cancer. Building on the strength of Princeton in the physical sciences and computation, we will innovate new methods for measuring and manipulating metabolism. We will explore the role of metabolism in cancer initiation, with obesity a major risk factor for endometrial, esophageal, liver, kidney, and pancreatic cancer. We will measure metabolic activity during tumorigenesis, from pre-malignant lesions to metastasis, in both tumors and their hosts, and between different cell types in the tumor microenvironment. The resulting knowledge will be used to develop new treatment regimens that manipulate metabolism to suppress tumor growth and augment antitumor immune response.
Related Publications
Xu X, Chen Z, Bartman CR, Xing X, Olszewski K, Rabinowitz JD. One-carbon unit supplementation fuels purine synthesis in tumor-infiltrating T cells and augments checkpoint blockade. Cell Chem Biol. 2024 May 16;31(5):932-943.e8. doi: 10.1016/j.chembiol.2024.04.007. PMID: 38759619.
Nucleotides perform important metabolic functions, carrying energy and feeding nucleic acid synthesis. Here, we use isotope tracing-mass spectrometry to quantitate contributions to purine nucleotides from salvage versus de novo synthesis. We further explore the impact of augmenting a key precursor for purine synthesis, one-carbon (1C) units. We show that tumors and tumor-infiltrating T cells (relative to splenic or lymph node T cells) synthesize purines de novo. Shortage of 1C units for T cell purine synthesis is accordingly a potential bottleneck for anti-tumor immunity. Supplementing 1C units by infusing formate drives formate assimilation into purines in tumor-infiltrating T cells. Orally administered methanol functions as a formate pro-drug, with deuteration enabling kinetic control of formate production. Safe doses of methanol raise formate levels and augment anti-PD-1 checkpoint blockade in MC38 tumors, tripling durable regressions. Thus, 1C deficiency can gate antitumor immunity and this metabolic checkpoint can be overcome with pharmacological 1C supplementation.
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.
Sawant A, Shi F, Lopes EC, Hu Z, Abdelfattah S, Baul J, Powers J, Hinrichs CS, Rabinowitz JD, Chan CS, Lattime EC, Ganesan S, White E. Immune Checkpoint Blockade Delays Cancer and Extends Survival in Murine DNA Polymerase Mutator Syndromes. bioRxiv [Preprint]. 2024 Jun 12:2024.06.10.597960. doi: 10.1101/2024.06.10.597960. PMID: 38915517; PMCID: PMC11195045.
Mutations in polymerases Pold1 and Pole exonuclease domains in humans are associated with increased cancer incidence, elevated tumor mutation burden (TMB) and response to immune checkpoint blockade (ICB). Although ICB is approved for treatment of several cancers, not all tumors with elevated TMB respond. Here we generated Pold1 and Pole proofreading mutator mice and show that ICB treatment of mice with high TMB tumors did not improve survival as only a subset of tumors responded. Similarly, introducing the mutator alleles into mice with Kras/p53 lung cancer did not improve survival, however, passaging mutator tumor cells in vitro without immune editing caused rejection in immune-competent hosts, demonstrating the efficiency by which cells with antigenic mutations are eliminated. Finally, ICB treatment of mutator mice earlier, before observable tumors delayed cancer onset, improved survival, and selected for tumors without aneuploidy, suggesting the use of ICB in individuals at high risk for cancer prevention.