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

Tsunekazu Oikawa, Eliane Wauthier, Timothy A. Dinh, Sara R. Selitsky, Andrea Reyna-Neyra, Guido Carpino, Ronald Levine, Vincenzo Cardinale, David Klimstra, Eugenio Gaudio, Domenico Alvaro, Nancy Carrasco, Praveen Sethupathy () and Lola M. Reid ()
Additional contact information
Tsunekazu Oikawa: Department of Cell Biology and Physiology
Eliane Wauthier: Department of Cell Biology and Physiology
Timothy A. Dinh: Department of Genetics
Sara R. Selitsky: Department of Genetics
Andrea Reyna-Neyra: Yale University School of Medicine
Guido Carpino: Human and Health Sciences, University of Rome ‘Foro Italico’
Ronald Levine: Greenwich Hospital
Vincenzo Cardinale: Fondazione Eleonora Lorillard Spencer Cenci, Polo Pontino, Viale dell'Universita 37, 00185 Rome, Italy
David Klimstra: Memorial Sloan Kettering Cancer Center
Eugenio Gaudio: Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome
Domenico Alvaro: Fondazione Eleonora Lorillard Spencer Cenci, Polo Pontino, Viale dell'Universita 37, 00185 Rome, Italy
Nancy Carrasco: Yale University School of Medicine
Praveen Sethupathy: Lineberger Comprehensive Cancer Center
Lola M. Reid: Department of Cell Biology and Physiology

Nature Communications, 2015, vol. 6, issue 1, 1-17

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9070

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