Breast Cancer-Derived Lung Metastases Show Increased Pyruvate Carboxylase-Dependent Anaplerosis

Cell Rep. 2016 Oct 11;17(3):837-848. doi: 10.1016/j.celrep.2016.09.042.


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.

Keywords: (13)C tracer analysis; TCA cycle anaplerosis; breast cancer; cancer metabolism; glycolytic metabolism; lung metastasis; microenvironment; mitochondrial pyruvate concentration; pyruvate carboxylase; pyruvate metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl Coenzyme A / metabolism
  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Breast Neoplasms / pathology*
  • Carbon Isotopes
  • Cell Compartmentation
  • Cell Line, Tumor
  • Citric Acid Cycle*
  • Cytosol / metabolism
  • Female
  • Humans
  • Isotope Labeling
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / secondary*
  • Mitochondria / metabolism
  • Pyruvate Carboxylase / metabolism*
  • Pyruvic Acid / metabolism
  • Tumor Microenvironment


  • Carbon Isotopes
  • Adenosine Diphosphate
  • Acetyl Coenzyme A
  • Pyruvic Acid
  • Adenosine Triphosphate
  • Pyruvate Carboxylase