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

doi:10.1016/j.celrep.2016.09.042

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

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

165 Scopus citations

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 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 language	English (US)
Pages (from-to)	837-848
Number of pages	12
Journal	Cell reports
Volume	17
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2016.09.042
State	Published - Oct 11 2016

Keywords

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)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2016.09.042

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@article{ac96ca41b7e642e68c4574688b6906b2,

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

author = "Stefan Christen and Doriane Lorendeau and Roberta Schmieder and Dorien Broekaert and Kristine Metzger and Koen Veys and Ilaria Elia and Buescher, {Joerg Martin} and Orth, {Martin Franz} and Davidson, {Shawn Michael} and Gr{\"u}newald, {Thomas Georg Philipp} and {De Bock}, Katrien and Fendt, {Sarah Maria}",

note = "Funding Information: We thank Prof. Metallo (UCSD) for providing raw data to their MPC publication; Prof. Mazzone and Mr. Bieniasz-Krzywiec (VIB) as well as Dr. Ghesqui{\`e}re (VIB) for advice on the 4T1 model and acetyl-CoA measurements, respectively; Prof. Vander Heiden (MIT) for providing the IDH mutant plasmids; and the VIB Bio Imaging Core for advice. D.L. is recipient of a VIB-Marie Curie fellowship. T.G.P.G. is supported by WiFoMed, the Daimler and Benz Foundation in cooperation with the Reinhard Frank Foundation, the Bettina-Br{\"a}u-Foundation, the Kind-Philipp-Foundation, the “Deutsche Stiftung f{\"u}r junge Erwachsene mit Krebs,” the Fritz-Thyssen Foundation (FTF-40.15.0.030MN), the Friedrich-Baur Foundation, and by the German Cancer Aid (DKH-111886 and DKH-70112257). S.-M.F. acknowledges funding support from Marie Curie-CIG, FWO-Odysseus II, Concern Foundation, FWO-Research Grants, KU-Leuven Methusalem co-funding, Eug{\`e}ne Yourassowsky Schenking, and Bayer Health Care. Publisher Copyright: {\textcopyright} 2016 The Author(s)",

year = "2016",

month = oct,

day = "11",

doi = "10.1016/j.celrep.2016.09.042",

language = "English (US)",

volume = "17",

pages = "837--848",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

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T1 - Breast Cancer-Derived Lung Metastases Show Increased Pyruvate Carboxylase-Dependent Anaplerosis

AU - Christen, Stefan

AU - Lorendeau, Doriane

AU - Schmieder, Roberta

AU - Broekaert, Dorien

AU - Metzger, Kristine

AU - Veys, Koen

AU - Elia, Ilaria

AU - Buescher, Joerg Martin

AU - Orth, Martin Franz

AU - Davidson, Shawn Michael

AU - Grünewald, Thomas Georg Philipp

AU - De Bock, Katrien

AU - Fendt, Sarah Maria

N1 - Funding Information: We thank Prof. Metallo (UCSD) for providing raw data to their MPC publication; Prof. Mazzone and Mr. Bieniasz-Krzywiec (VIB) as well as Dr. Ghesquière (VIB) for advice on the 4T1 model and acetyl-CoA measurements, respectively; Prof. Vander Heiden (MIT) for providing the IDH mutant plasmids; and the VIB Bio Imaging Core for advice. D.L. is recipient of a VIB-Marie Curie fellowship. T.G.P.G. is supported by WiFoMed, the Daimler and Benz Foundation in cooperation with the Reinhard Frank Foundation, the Bettina-Bräu-Foundation, the Kind-Philipp-Foundation, the “Deutsche Stiftung für junge Erwachsene mit Krebs,” the Fritz-Thyssen Foundation (FTF-40.15.0.030MN), the Friedrich-Baur Foundation, and by the German Cancer Aid (DKH-111886 and DKH-70112257). S.-M.F. acknowledges funding support from Marie Curie-CIG, FWO-Odysseus II, Concern Foundation, FWO-Research Grants, KU-Leuven Methusalem co-funding, Eugène Yourassowsky Schenking, and Bayer Health Care. Publisher Copyright: © 2016 The Author(s)

PY - 2016/10/11

Y1 - 2016/10/11

N2 - 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.

AB - 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.

KW - C tracer analysis

KW - breast cancer

KW - cancer metabolism

KW - glycolytic metabolism

KW - lung metastasis

KW - microenvironment

KW - mitochondrial pyruvate concentration

KW - pyruvate carboxylase

KW - pyruvate metabolism

KW - TCA cycle anaplerosis

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DO - 10.1016/j.celrep.2016.09.042

M3 - Article

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AN - SCOPUS:84992195909

SN - 2211-1247

VL - 17

SP - 837

EP - 848

JO - Cell reports

JF - Cell reports

IS - 3

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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