Tracing glucose catabolism in human triple negative breast cancer tumors

Triple negative breast cancer (TNBC) is an aggressive tumor type for which few targeted treatments exist. Altered tumor metabolism may provide novel diagnostic and therapeutic opportunities. Recent genetic analyses in TNBC demonstrate augmented expression of pathways related to glucose metabolism, including glycolysis, the pentose phosphate (PPP), and serine biosynthetic pathways. No studies, however, have directly probed how glucose is utilized by TNBCs in vivo. Here, we trace these metabolic fates by infusing TNBC patients with isotopically labeled 1,2-13C-glucose, a tracer that can determine which of these pathways predominate. Upon achieving stable tracer enrichment in serum, patient primary TNBC biopsies were collected and flash frozen. Subsequent analysis by liquid chromatography mass spectroscopy (LC-MS) revealed most TNBC tumors locally ferment glucose to lactate, with limited exchange of pyruvate/lactate with the systemic circulation. This contrasts with lung cancer, where pyruvate/lactate exchange is extensive. In addition, isotopic labeling patterns indicate that glycolysis dominates the PPP in terms of total flux. Nevertheless, ribose-phosphate for nucleotide synthesis consistently arises from the oxidative branch of the PPP. Furthermore, a subset of patients demonstrated high levels of de novo serine production. To better understand these observations, next generation sequencing (NGS) and reverse phase protein array (RPPA) analyses on adjacent biopsies from these patients are underway. Together, these findings provide the first comprehensive in vivo characterization of glucose metabolism in TNBC and raise the potential to use tracing to guide development of metabolic therapeutics. Citation Format: Jonathan Michael Ghergurovich, Joyce O’Shaughnessy, Maren K Levin, Aaron Killian, William Hendricks, Virginia Espina, Joshua D Rabinowitz. Tracing glucose catabolism in human triple negative breast cancer tumors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-02-06.