Metabolic Reprogramming and Dependencies Associated with Epithelial Cancer Stem Cells Independent of the Epithelial‐Mesenchymal Transition Program

• Published in: Stem cells (Dayton, Ohio) Ohio), 2016-05, Vol.34 (5), p.1163-1176
• Main Authors: Aguilar, Esther, Marin de Mas, Igor, Zodda, Erika, Marin, Silvia, Morrish, Fionnuala, Selivanov, Vitaly, Meca‐Cortés, Óscar, Delowar, Hossain, Pons, Mònica, Izquierdo, Inés, Celià‐Terrassa, Toni, de Atauri, Pedro, Centelles, Josep J., Hockenbery, David, Thomson, Timothy M., Cascante, Marta
• Format: Article
• Language: English
• Subjects: Amino acids; Amino Acids - metabolism; Cancer; Cancer stem cells; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Citric Acid Cycle - drug effects; Citric Acid Cycle - genetics; Disease Progression; Energy sources; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Epithelial‐mesenchymal transition; Fatty Acids - biosynthesis; Gene Expression Profiling; Genes, Neoplasm; Glucose - metabolism; Glutaminolysis; Glycolysis - drug effects; Glycolysis - genetics; Humans; Hydrogen-Ion Concentration; Mesoderm - pathology; Metabolic flux analysis; Metabolism; Metabolomics; Metastasis; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial metabolism; NADP - metabolism; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oxidative Stress - drug effects; Prostate cancer; Pyruvate Dehydrogenase Complex - metabolism; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Spheroids, Cellular - pathology; Stem cells; Transcription, Genetic - drug effects; Warburg effect
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2286

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