Breast Cancer-Derived Lung Metastases Show Increased Pyruvate Carboxylase-Dependent Anaplerosis
Stefan Christen,
Doriane Lorendeau,
Roberta Schmieder,
Dorien Broekaert,
Kristine Metzger,
Koen Veys,
Ilaria Elia,
Joerg Martin Buescher,
Martin Franz Orth,
Shawn Michael Davidson,
Thomas Georg Philipp Grünewald,
Katrien De Bock,
Sarah-Maria Fendt
Affiliations
Stefan Christen
Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium
Doriane Lorendeau
Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium
Roberta Schmieder
Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium
Dorien Broekaert
Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium
Kristine Metzger
Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium
Koen Veys
Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology (KU Leuven) and Vesalius Research Center (VIB), Herestraat 49, 3000 Leuven, Belgium
Ilaria Elia
Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium
Joerg Martin Buescher
Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium
Martin Franz Orth
Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, LMU Munich, Thalkirchner Strasse 36, 80337 Munich, Germany
Shawn Michael Davidson
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
Thomas Georg Philipp Grünewald
Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, LMU Munich, Thalkirchner Strasse 36, 80337 Munich, Germany
Katrien De Bock
Laboratory of Exercise and Health, Department of Health Sciences and Technology, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland
Sarah-Maria Fendt
Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium
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 vivo 13C 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.
