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.
Highlights
The aetiology of human fibrolamellar hepatocellular carcinomas, cancers occurring increasingly in children to young adults, is poorly understood
Cells from 4 of the liters were delivered to the Reid lab at University of North Carolina (UNC) and were cultured in Kubota’s Medium (KM), a serum-free medium found effective for culture selection of endodermal stem/progenitors[7,11,15,16]
The ability to analyse the variables contributing to the pathogenesis for hFL-HCCs and to search for effective treatments has been severely restricted by the lack of any model system, forcing investigators to deal entirely with primary tumour samples, ones extremely difficult to obtain
Summary
The aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs), cancers occurring increasingly in children to young adults, is poorly understood. 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. The transplantable, subcutaneous tumours were aggressive in being able to penetrate through the body wall into the peritoneum They were nodular and difficult to mince. If transplanted intraperitoneally (Fig. 1b), ascites tumours formed after B8 weeks and gave rise to nodules on all serosal surfaces within the abdomen
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