title: Metabolic Reprogramming and Dependencies Associated with Epithelial Cancer Stem Cells Independent of the Epithelial-Mesenchymal Transition Program.
abstract: In solid tumors, cancer stem cells (CSCs) can arise independently of epithelial-mesenchymal transition (EMT). In spite of recent efforts, the metabolic reprogramming associated with CSC phenotypes uncoupled from EMT is poorly understood. Here, by using metabolomic and fluxomic approaches, we identify major metabolic profiles that differentiate metastatic prostate epithelial CSCs (e-CSCs) from non-CSCs expressing a stable EMT. We have found that the e-CSC program in our cellular model is characterized by a high plasticity in energy substrate metabolism, including an enhanced Warburg effect, a greater carbon and energy source flexibility driven by fatty acids and amino acid metabolism and an essential reliance on the proton buffering capacity conferred by glutamine metabolism. An analysis of transcriptomic data yielded a metabolic gene signature for our e-CSCs consistent with the metabolomics and fluxomics analyses that correlated with tumor progression and metastasis in prostate cancer and in 11 additional cancer types. Interestingly, an integrated metabolomics, fluxomics, and transcriptomics analysis allowed us to identify key metabolic players regulated at the post-transcriptional level, suggesting potential biomarkers and therapeutic targets to effectively forestall metastasis. Stem Cells 2016;34:1163-1176.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Diagonal 643, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Aguilar
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Diagonal 643, Barcelona, Spain.
authors.forename: Igor
authors.initials: I
authors.lastname: Marin de Mas
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Diagonal 643, Barcelona, Spain.|Department of Cell Biology, Molecular Biology Institute, National Research Council (IBMB-CSIC), Barcelona, Spain.
authors.forename: Erika
authors.initials: E
authors.lastname: Zodda
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Diagonal 643, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marin
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Fionnuala
authors.initials: F
authors.lastname: Morrish
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Diagonal 643, Barcelona, Spain.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Selivanov
authors.affiliation: Department of Cell Biology, Molecular Biology Institute, National Research Council (IBMB-CSIC), Barcelona, Spain.
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Meca-Cortés
authors.affiliation: Department of Cell Biology, Molecular Biology Institute, National Research Council (IBMB-CSIC), Barcelona, Spain.
authors.forename: Hossain
authors.initials: H
authors.lastname: Delowar
authors.affiliation: Department of Cell Biology, Molecular Biology Institute, National Research Council (IBMB-CSIC), Barcelona, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Pons
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Diagonal 643, Barcelona, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Izquierdo
authors.affiliation: Department of Cell Biology, Molecular Biology Institute, National Research Council (IBMB-CSIC), Barcelona, Spain.
authors.forename: Toni
authors.initials: T
authors.lastname: Celià-Terrassa
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Diagonal 643, Barcelona, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: de Atauri
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Diagonal 643, Barcelona, Spain.
authors.forename: Josep J
authors.initials: JJ
authors.lastname: Centelles
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hockenbery
authors.affiliation: Department of Cell Biology, Molecular Biology Institute, National Research Council (IBMB-CSIC), Barcelona, Spain.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Thomson
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Diagonal 643, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cascante
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002952:Citric Acid Cycle / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008648:Mesoderm / Q000473:pathology; D055432:Metabolomics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000596:Amino Acids; D005227:Fatty Acids; D011768:Pyruvate Dehydrogenase Complex; D009249:NADP; D005947:Glucose
keywords: Cancer stem cells; Epithelial-mesenchymal transition; Glutaminolysis; Metabolic flux analysis; Mitochondrial metabolism; Warburg effect