title: The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells.
abstract: OBJECTIVE
  Cancer stem cells (CSCs) represent the root of many solid cancers including pancreatic ductal adenocarcinoma, are highly chemoresistant and represent the cellular source for disease relapse. However the mechanisms involved in these processes still need to be fully elucidated. Understanding the mechanisms implicated in chemoresistance and metastasis of pancreatic cancer is critical to improving patient outcomes.
  
  
  METHODS
  Micro-RNA (miRNA) expression analyses were performed to identify functionally defining epigenetic signatures in pancreatic CSC-enriched sphere-derived cells and gemcitabine-resistant pancreatic CSCs.
  
  
  RESULTS
  We found the miR-17-92 cluster to be downregulated in chemoresistant CSCs versus non-CSCs and demonstrate its crucial relevance for CSC biology. In particular, overexpression of miR-17-92 reduced CSC self-renewal capacity, in vivo tumourigenicity and chemoresistance by targeting multiple NODAL/ACTIVIN/TGF-β1 signalling cascade members as well as directly inhibiting the downstream targets p21, p57 and TBX3. Overexpression of miR-17-92 translated into increased CSC proliferation and their eventual exhaustion via downregulation of p21 and p57. Finally, the translational impact of our findings could be confirmed in preclinical models for pancreatic cancer.
  
  
  CONCLUSIONS
  Our findings therefore identify the miR-17-92 cluster as a functionally determining family of miRNAs in CSCs, and highlight the putative potential of developing modulators of this cluster to overcome drug resistance in pancreatic CSCs.
authors.affiliation: Stem Cells & Cancer Group, CNIO, Madrid, Spain.
authors.forename: Michele
authors.initials: M
authors.lastname: Cioffi
authors.affiliation: Stem Cells & Cancer Group, CNIO, Madrid, Spain.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Trabulo
authors.affiliation: Stem Cells & Cancer Group, CNIO, Madrid, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Sanchez-Ripoll
authors.affiliation: Stem Cells & Cancer Group, CNIO, Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Miranda-Lorenzo
authors.affiliation: Stem Cells & Cancer Group, CNIO, Madrid, Spain.
authors.forename: Enza
authors.initials: E
authors.lastname: Lonardo
authors.affiliation: Stem Cells & Cancer Group, CNIO, Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Dorado
authors.affiliation: Stem Cells & Cancer Group, CNIO, Madrid, Spain Viral Vector Unit, Spanish National Cardiovascular Research Centre (CNIC), Madrid, Spain.
authors.forename: Catarina
authors.initials: C
authors.lastname: Reis Vieira
authors.affiliation: Viral Vector Unit, Spanish National Cardiovascular Research Centre (CNIC), Madrid, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Ramirez
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.affiliation: Stem Cells & Cancer Group, CNIO, Madrid, Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Aicher
authors.affiliation: Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, D-44801 Bochum, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Hahn
authors.affiliation: Stem Cells & Cancer Group, CNIO, Madrid, Spain.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sainz
authors.affiliation: Stem Cells & Cancer Group, CNIO, Madrid, Spain Barts Cancer Institute, Centre for Stem Cells in Cancer & Ageing, Queen Mary University of London, London, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D000066673:Cell Self Renewal; D002471:Cell Transformation, Neoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D055457:Nodal Protein / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050761:Cyclin-Dependent Kinase Inhibitor p57; C568997:MIR17HG, human; D035683:MicroRNAs; D055457:Nodal Protein; D062085:RNA, Long Noncoding; D020825:T-Box Domain Proteins; C106884:TBX3 protein, human; D053773:Transforming Growth Factor beta1; D003841:Deoxycytidine; D028341:Activins; D000093542:Gemcitabine
keywords: CELL CYCLE CONTROL; DRUG RESISTANCE; INTRACELLULAR SIGNALING; PANCREATIC CANCER; STEM CELLS