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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

165 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)837-848
Number of pages12
JournalCell reports
Issue number3
StatePublished - Oct 11 2016


  • C tracer analysis
  • breast cancer
  • cancer metabolism
  • glycolytic metabolism
  • lung metastasis
  • microenvironment
  • mitochondrial pyruvate concentration
  • pyruvate carboxylase
  • pyruvate metabolism
  • TCA cycle anaplerosis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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