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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

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

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