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

Autor:	Ghergurovich JM; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA., Lang JD; Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA., Levin MK; Baylor Scott & White Research Institute, Dallas, TX 75204, USA., Briones N; Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA., Facista SJ; Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA., Mueller C; Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA., Cowan AJ; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA., McBride MJ; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA., Rodriguez ESR; Baylor Scott & White Research Institute, Dallas, TX 75204, USA., Killian A; Baylor Scott & White Research Institute, Dallas, TX 75204, USA., Dao T; Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX 75246, USA., Lamont J; Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX 75246, USA., Barron A; Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX 75246, USA., Su X; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901 USA., Hendricks WPD; Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA., Espina V; Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA., Von Hoff DD; Molecular Medicine Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA., O'Shaughnessy J; Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX 75246, USA., Rabinowitz JD; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
Jazyk:	angličtina
Zdroj:	Med (New York, N.Y.) [Med] 2021 Jun 11; Vol. 2 (6), pp. 736-754. Date of Electronic Publication: 2021 Apr 14.
DOI:	10.1016/j.medj.2021.03.009
Abstrakt:	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- 13 C]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- 13 C]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.
Databáze:	MEDLINE
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