title: Metabolic plasticity of metastatic breast cancer cells: adaptation to changes in the microenvironment.
abstract: Cancer cells adapt their metabolism during tumorigenesis. We studied two isogenic breast cancer cells lines (highly metastatic 4T1; nonmetastatic 67NR) to identify differences in their glucose and glutamine metabolism in response to metabolic and environmental stress. Dynamic magnetic resonance spectroscopy of (13)C-isotopomers showed that 4T1 cells have higher glycolytic and tricarboxylic acid (TCA) cycle flux than 67NR cells and readily switch between glycolysis and oxidative phosphorylation (OXPHOS) in response to different extracellular environments. OXPHOS activity increased with metastatic potential in isogenic cell lines derived from the same primary breast cancer: 4T1 > 4T07 and 168FARN (local micrometastasis only) > 67NR. We observed a restricted TCA cycle flux at the succinate dehydrogenase step in 67NR cells (but not in 4T1 cells), leading to succinate accumulation and hindering OXPHOS. In the four isogenic cell lines, environmental stresses modulated succinate dehydrogenase subunit A expression according to metastatic potential. Moreover, glucose-derived lactate production was more glutamine dependent in cell lines with higher metastatic potential. These studies show clear differences in TCA cycle metabolism between 4T1 and 67NR breast cancer cells. They indicate that metastases-forming 4T1 cells are more adept at adjusting their metabolism in response to environmental stress than isogenic, nonmetastatic 67NR cells. We suggest that the metabolic plasticity and adaptability are more important to the metastatic breast cancer phenotype than rapid cell proliferation alone, which could 1) provide a new biomarker for early detection of this phenotype, possibly at the time of diagnosis, and 2) lead to new treatment strategies of metastatic breast cancer by targeting mitochondrial metabolism.
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA.
authors.forename: Rui V
authors.initials: RV
authors.lastname: Simões
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA.
authors.forename: Inna S
authors.initials: IS
authors.lastname: Serganova
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kruchevsky
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA.
authors.forename: Avigdor
authors.initials: A
authors.lastname: Leftin
authors.affiliation: Division of Nutritional Sciences, Cornell University, 14853, Ithaca, NY, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shestov
authors.affiliation: Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA.
authors.forename: Howard T
authors.initials: HT
authors.lastname: Thaler
authors.affiliation: NMR Core Facility, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA.
authors.forename: George
authors.initials: G
authors.lastname: Sukenick
authors.affiliation: Division of Nutritional Sciences, Cornell University, 14853, Ithaca, NY, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA; Department of Radiology, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA; Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Blasberg
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA; Department of Radiology, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA; Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA; Weill Cornell Medical College, Cornell University, 10065, New York, NY, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Koutcher
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA. Electronic address: ackerste@mskcc.org.
authors.forename: Ellen
authors.initials: E
authors.lastname: Ackerstaff
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D066241:Carbon-13 Magnetic Resonance Spectroscopy / Q000379:methods; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D005973:Glutamine / Q000378:metabolism* / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D010743:Phospholipids; D005973:Glutamine; D005947:Glucose