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Nat Commun. 2015 Oct 6;6:8070. doi: 10.1038/ncomms9070.

Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells.

Author information

  • 1Department of Cell Biology and Physiology, Chapel Hill, North Carolina 27599, USA.
  • 2Program in Molecular Biology and Biotechnology, Chapel Hill, North Carolina 27599, USA.
  • 3Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
  • 4Department of Genetics, Chapel Hill, North Carolina 27599, USA.
  • 5Curriculum in Genetics and Molecular Biology, Chapel Hill, North Carolina 27599, USA.
  • 6MD-PhD Program, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA.
  • 7Curriculum in Bioinformatics and Computational Biology, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA.
  • 8Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
  • 9Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome 'Foro Italico', Piazza Lauro De Bosis 6, 00151 Rome, Italy.
  • 10Greenwich Hospital, 5 Perryridge Road, Greenwich, Connecticut 06830, USA.
  • 11Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut, 06510 USA.
  • 12Division of Gastroenterology, Department of Scienze e Biotecnologie Medico-Chirurgiche, Fondazione Eleonora Lorillard Spencer Cenci, Polo Pontino, Viale dell'Universita 37, 00185 Rome, Italy.
  • 13Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
  • 14Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy.

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.

Comment in

PMID:
26437858
PMCID:
PMC4600730
DOI:
10.1038/ncomms9070
[PubMed - indexed for MEDLINE]
Free PMC Article

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