title: MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells.
abstract: The anti-diabetic drug metformin targets pancreatic cancer stem cells (CSCs), but not their differentiated progenies (non-CSCs), which may be related to distinct metabolic phenotypes. Here we conclusively demonstrate that while non-CSCs were highly glycolytic, CSCs were dependent on oxidative metabolism (OXPHOS) with very limited metabolic plasticity. Thus, mitochondrial inhibition, e.g., by metformin, translated into energy crisis and apoptosis. However, resistant CSC clones eventually emerged during treatment with metformin due to their intermediate glycolytic/respiratory phenotype. Mechanistically, suppression of MYC and subsequent increase of PGC-1α were identified as key determinants for the OXPHOS dependency of CSCs, which was abolished in resistant CSC clones. Intriguingly, no resistance was observed for the mitochondrial ROS inducer menadione and resistance could also be prevented/reversed for metformin by genetic/pharmacological inhibition of MYC. Thus, the specific metabolic features of pancreatic CSCs are amendable to therapeutic intervention and could provide the basis for developing more effective therapies to combat this lethal cancer.
authors.affiliation: Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK; Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. Electronic address: p.sancho@qmul.ac.uk.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sancho
authors.affiliation: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Emma
authors.initials: E
authors.lastname: Burgos-Ramos
authors.affiliation: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Tavera
authors.affiliation: Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Bou Kheir
authors.affiliation: Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Petra
authors.initials: P
authors.lastname: Jagust
authors.affiliation: Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schoenhals
authors.affiliation: Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: David
authors.initials: D
authors.lastname: Barneda
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratories, The Ridgeway, London NW7 1AA, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Sellers
authors.affiliation: Spectroscopy and NMR Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Campos-Olivas
authors.affiliation: Bioinformatics Unit and Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Graña
authors.affiliation: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Catarina R
authors.initials: CR
authors.lastname: Viera
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratories, The Ridgeway, London NW7 1AA, UK.
authors.forename: Mariia
authors.initials: M
authors.lastname: Yuneva
authors.affiliation: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sainz
authors.affiliation: Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK; Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. Electronic address: c.heeschen@qmul.ac.uk.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D015723:Gene Library; D006023:Glycoproteins; D006801:Humans; D008687:Metformin / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010455:Peptides; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; C486497:PPARGC1A protein, human; D010455:Peptides; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D024483:Vitamin K 3; D008687:Metformin