title: Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells.
abstract: The aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs), cancers occurring increasingly in children to young adults, is poorly understood. We present a transplantable tumour line, maintained in immune-compromised mice, and validate it as a bona fide model of hFL-HCCs by multiple methods. RNA-seq analysis confirms the presence of a fusion transcript (DNAJB1-PRKACA) characteristic of hFL-HCC tumours. The hFL-HCC tumour line is highly enriched for cancer stem cells as indicated by limited dilution tumourigenicity assays, spheroid formation and flow cytometry. Immunohistochemistry on the hFL-HCC model, with parallel studies on 27 primary hFL-HCC tumours, provides robust evidence for expression of endodermal stem cell traits. Transcriptomic analyses of the tumour line and of multiple, normal hepatic lineage stages reveal a gene signature for hFL-HCCs closely resembling that of biliary tree stem cells--newly discovered precursors for liver and pancreas. This model offers unprecedented opportunities to investigate mechanisms underlying hFL-HCCs pathogenesis and potential therapies.
authors.affiliation: Department of Cell Biology and Physiology, Chapel Hill, North Carolina 27599, USA.|Program in Molecular Biology and Biotechnology, Chapel Hill, North Carolina 27599, USA.|Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Oikawa
authors.affiliation: Department of Cell Biology and Physiology, Chapel Hill, North Carolina 27599, USA.|Program in Molecular Biology and Biotechnology, Chapel Hill, North Carolina 27599, USA.|Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
authors.forename: Eliane
authors.initials: E
authors.lastname: Wauthier
authors.affiliation: Department of Genetics, Chapel Hill, North Carolina 27599, USA.|Curriculum in Genetics and Molecular Biology, Chapel Hill, North Carolina 27599, USA.|MD-PhD Program, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Dinh
authors.affiliation: Department of Genetics, Chapel Hill, North Carolina 27599, USA.|Curriculum in Bioinformatics and Computational Biology, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Selitsky
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Reyna-Neyra
authors.affiliation: Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome 'Foro Italico', Piazza Lauro De Bosis 6, 00151 Rome, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Carpino
authors.affiliation: Greenwich Hospital, 5 Perryridge Road, Greenwich, Connecticut 06830, USA.|Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut, 06510 USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Levine
authors.affiliation: Division of Gastroenterology, Department of Scienze e Biotecnologie Medico-Chirurgiche, Fondazione Eleonora Lorillard Spencer Cenci, Polo Pontino, Viale dell'Universita 37, 00185 Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cardinale
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: David
authors.initials: D
authors.lastname: Klimstra
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.affiliation: Division of Gastroenterology, Department of Scienze e Biotecnologie Medico-Chirurgiche, Fondazione Eleonora Lorillard Spencer Cenci, Polo Pontino, Viale dell'Universita 37, 00185 Rome, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Carrasco
authors.affiliation: Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.|Department of Genetics, Chapel Hill, North Carolina 27599, USA.|Curriculum in Genetics and Molecular Biology, Chapel Hill, North Carolina 27599, USA.|Curriculum in Bioinformatics and Computational Biology, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Sethupathy
authors.affiliation: Department of Cell Biology and Physiology, Chapel Hill, North Carolina 27599, USA.|Program in Molecular Biology and Biotechnology, Chapel Hill, North Carolina 27599, USA.|Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
authors.forename: Lola M
authors.initials: LM
authors.lastname: Reid
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D050506:Mutant Chimeric Proteins / Q000235:genetics*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C494647:DNAJB1 protein, human; D050956:HSP40 Heat-Shock Proteins; D050506:Mutant Chimeric Proteins; D012333:RNA, Messenger; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human