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Christen, Stefan; Lorendeau, Doriane; Schmieder, Roberta; Broekaert, Dorien; Metzger, Kristine; Veys, Koen; Elia, Ilaria; Buescher, Joerg Martin; Orth, Martin Franz; Davidson, Shawn Michael; Grünewald, Thomas Georg Philipp; De Bock, Katrien; Fendt, Sarah-Maria
Cell reports, 10/2016, Volume: 17, Issue: 3Journal Article
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. Display omitted •Lung metastases have higher PC-dependent anaplerosis than primary breast cancers•PC-dependent anaplerosis is a function of the in vivo microenvironment•Pyruvate to glutamine availability is increased in the in vivo lung microenvironment•Compartment-specific pyruvate distributions can be inferred from 13C labeling patterns Christen et al. find that primary breast cancers and their resulting lung metastases use different modes of TCA cycle anaplerosis. Lung metastases increase PC-dependent anaplerosis in response to the in vivo lung microenvironment. Mechanistically, this response is mediated by alterations in PC expression and mitochondrial pyruvate concentrations.
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