Local production of lactate, ribose phosphate, and amino acids within human triple-negative breast cancer.

TitleLocal production of lactate, ribose phosphate, and amino acids within human triple-negative breast cancer.
Publication TypeJournal Article
Year of Publication2021
AuthorsGhergurovich, JM, Lang, JD, Levin, MK, Briones, N, Facista, SJ, Mueller, C, Cowan, AJ, McBride, MJ, Rodriguez, ESan Roman, Killian, A, Dao, T, Lamont, J, Barron, A, Su, X, Hendricks, WPD, Espina, V, Von Hoff, DD, O'Shaughnessy, J, Rabinowitz, JD
JournalMed (N Y)
Volume2
Issue6
Pagination736-754
Date Published2021 Jun 11
ISSN2666-6340
Abstract

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 IV 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 exceeds 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 TCA cycle locally within human breast tumors.

DOI10.1016/j.medj.2021.03.009
Alternate JournalMed (N Y)
PubMed ID34223403
PubMed Central IDPMC8248508
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
P30 CA072720 / CA / NCI NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States