Med | May 14, 2021

Ghergurovich JM, Lang JD, Levin MK, Briones N, Facista SJ, Mueller C, Cowan AJ, McBride MJ, San Roman Rodriguez E, Killian A, Dao T, Lamont J, Barron A, Su X, Hendricks WPD, Espina V, Von Hoff DD, O’Shaughnessy J and Rabinowitz JD

Med 2, 1–19

DOI: https://doi.org/10.1016/j.medj.2021.03.009

SUMMARY

Background: Upregulated glucose metabolism is a common feature of tumors. Glucose can be broken down by either glycolysis or the oxidative pentose phosphate pathway (oxPPP). The relative usage within tumors of these catabolic pathways remains unclear. Similarly, the extent to which tumors make biomass precursors from glucose, versus take them up from the circulation, is incompletely defined.

Methods: We explore human triple-negative breast cancer (TNBC) metabolism by isotope tracing with [1,2-13C]glucose, a tracer that differentiates glycolytic versus oxPPP catabolism and reveals glucose-driven anabolism. Patients enrolled in clinical trial NCT03457779 and received intravenous (i.v.) infusion of [1,2-13C]glucose during core biopsy of their primary TNBC. Tumor samples were analyzed for metabolite labeling by liquid chromatography-mass spectrometry (LC-MS). Genomic and proteomic analyses were performed and related to observed metabolic fluxes.

Findings: TNBC ferments glucose to lactate, with glycolysis dominant over the oxPPP. Most ribose phosphate is nevertheless produced by oxPPP. Glucose also feeds amino acid synthesis, including of serine, glycine, aspartate, glutamate, proline, and glutamine (but not asparagine). Downstream in glycolysis, tumor pyruvate and lactate labeling exceed that found in serum, indicating that lactate exchange via monocarboxylic
transporters is less prevalent in human TNBC compared with most normal tissues or non-small cell lung cancer.

Conclusions: Glucose directly feeds ribose phosphate, amino acid synthesis, lactate, and the tricarboxylic acid (TCA) cycle locally within human breast tumors.