Metabolic re-wiring of isogenic breast epithelial cell lines following epithelial to mesenchymal transition.
Epithelial to mesenchymal transition (EMT) has implications in tumor progression and metastasis. Metabolic alterations have been described in cancer development but studies focused on the metabolic re-wiring that takes place during EMT are still limited. We performed metabolomics profiling of a breast epithelial cell line and its EMT derived mesenchymal phenotype to create genome-scale metabolic models descriptive of both cell lines. Glycolysis and OXPHOS were higher in the epithelial phenotype while amino acid anaplerosis and fatty acid oxidation fueled the mesenchymal phenotype. Through comparative bioinformatics analysis, PPAR-γ1, PPAR- γ2 and AP-1 were found to be the most influential transcription factors associated with metabolic re-wiring. In silico gene essentiality analysis predicts that the LAT1 neutral amino acid transporter is essential for mesenchymal cell survival. Our results define metabolic traits that distinguish an EMT derived mesenchymal cell line from its epithelial progenitor and may have implications in cancer progression and metastasis. Furthermore, the tools presented here can aid in identifying critical metabolic nodes that may serve as therapeutic targets aiming to prevent EMT and inhibit metastatic dissemination.
Center for Systems Biology, University of Iceland, Reykjavik, Iceland; Biomedical Center, University of Iceland, Reykjavík, Iceland. Electronic address: skarph@hi.is.
Skarphedinn
S
Halldorsson
Center for Systems Biology, University of Iceland, Reykjavik, Iceland; Biomedical Center, University of Iceland, Reykjavík, Iceland.
Neha
N
Rohatgi
Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
Manuela
M
Magnusdottir
Center for Systems Biology, University of Iceland, Reykjavik, Iceland; Biomedical Center, University of Iceland, Reykjavík, Iceland.
Kumari Sonal
KS
Choudhary
Biomedical Center, University of Iceland, Reykjavík, Iceland; Department of Anatomy, Faculty of Medicine, and Department of Laboratory Hematology, University Hospital, Reykjavik, Iceland.
Thorarinn
T
Gudjonsson
Department of Medical Biology, UiT - The Arctic University of Norway, Tromsø, Norway.
Erik
E
Knutsen
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway; Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Anna
A
Barkovskaya
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway.
Bylgja
B
Hilmarsdottir
Department of Medical Biology, UiT - The Arctic University of Norway, Tromsø, Norway.
Maria
M
Perander
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway; Department of Pharmacy, UiT - The Arctic University of Norway, Tromsø, Norway.
Gunhild M
GM
Mælandsmo
Center for Systems Biology, University of Iceland, Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Steinn
S
Gudmundsson
Center for Systems Biology, University of Iceland, Reykjavik, Iceland; Biomedical Center, University of Iceland, Reykjavík, Iceland.
Óttar
Ó
Rolfsson
D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D055432:Metabolomics
Breast cancer; EMT; Genome scale models; Metabolism