title: Breast Cancer-Derived Lung Metastases Show Increased Pyruvate Carboxylase-Dependent Anaplerosis.
abstract: Cellular proliferation depends on refilling the tricarboxylic acid (TCA) cycle to support biomass production (anaplerosis). The two major anaplerotic pathways in cells are pyruvate conversion to oxaloacetate via pyruvate carboxylase (PC) and glutamine conversion to α-ketoglutarate. Cancers often show an organ-specific reliance on either pathway. However, it remains unknown whether they adapt their mode of anaplerosis when metastasizing to a distant organ. We measured PC-dependent anaplerosis in breast-cancer-derived lung metastases compared to their primary cancers using in vivo13C tracer analysis. We discovered that lung metastases have higher PC-dependent anaplerosis compared to primary breast cancers. Based on in vitro analysis and a mathematical model for the determination of compartment-specific metabolite concentrations, we found that mitochondrial pyruvate concentrations can promote PC-dependent anaplerosis via enzyme kinetics. In conclusion, we show that breast cancer cells proliferating as lung metastases activate PC-dependent anaplerosis in response to the lung microenvironment.
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Christen
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Doriane
authors.initials: D
authors.lastname: Lorendeau
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Roberta
authors.initials: R
authors.lastname: Schmieder
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Dorien
authors.initials: D
authors.lastname: Broekaert
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Kristine
authors.initials: K
authors.lastname: Metzger
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology (KU Leuven) and Vesalius Research Center (VIB), Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Veys
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Elia
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Joerg Martin
authors.initials: JM
authors.lastname: Buescher
authors.affiliation: Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, LMU Munich, Thalkirchner Strasse 36, 80337 Munich, Germany.
authors.forename: Martin Franz
authors.initials: MF
authors.lastname: Orth
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
authors.forename: Shawn Michael
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, LMU Munich, Thalkirchner Strasse 36, 80337 Munich, Germany.
authors.forename: Thomas Georg Philipp
authors.initials: TG
authors.lastname: Grünewald
authors.affiliation: Laboratory of Exercise and Health, Department of Health Sciences and Technology, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
authors.forename: Katrien
authors.initials: K
authors.lastname: De Bock
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium. Electronic address: sarah-maria.fendt@vib-kuleuven.be.
authors.forename: Sarah-Maria
authors.initials: SM
authors.lastname: Fendt
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D002247:Carbon Isotopes; D002451:Cell Compartmentation; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006801:Humans; D007553:Isotope Labeling; D008175:Lung Neoplasms / Q000201:enzymology* / Q000556:secondary*; D008928:Mitochondria / Q000378:metabolism; D011766:Pyruvate Carboxylase / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D002247:Carbon Isotopes; D000244:Adenosine Diphosphate; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D011766:Pyruvate Carboxylase
keywords: (13)C tracer analysis; TCA cycle anaplerosis; breast cancer; cancer metabolism; glycolytic metabolism; lung metastasis; microenvironment; mitochondrial pyruvate concentration; pyruvate carboxylase; pyruvate metabolism