Oikawa Tsunekazu, Wauthier Eliane, Dinh Timothy A, Selitsky Sara R, Reyna-Neyra Andrea, Carpino Guido, Levine Ronald, Cardinale Vincenzo, Klimstra David, Gaudio Eugenio, Alvaro Domenico, Carrasco Nancy, Sethupathy Praveen, Reid Lola M
Department of Cell Biology and Physiology, Chapel Hill, North Carolina 27599, USA.
Program in Molecular Biology and Biotechnology, Chapel Hill, North Carolina 27599, USA.
Nat Commun. 2015 Oct 6;6:8070. doi: 10.1038/ncomms9070.
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.
人类纤维板层型肝细胞癌（hFL - HCCs）在儿童至青年成年人中越来越多地出现，其病因尚不清楚。我们展示了一种可移植的肿瘤细胞系，在免疫缺陷小鼠中维持，并通过多种方法将其验证为hFL - HCCs的真实模型。RNA测序分析证实了hFL - HCC肿瘤特征性融合转录本（DNAJB1 - PRKACA）的存在。有限稀释致瘤性试验、球体形成和流式细胞术表明，hFL - HCC肿瘤细胞系高度富集癌症干细胞。对hFL - HCC模型进行免疫组织化学分析，并对27例原发性hFL - HCC肿瘤进行平行研究，为内胚层干细胞特征的表达提供了有力证据。对肿瘤细胞系和多个正常肝谱系阶段进行转录组分析，揭示了hFL - HCCs的基因特征，与胆管树干细胞的特征非常相似，胆管树干细胞是新发现的肝脏和胰腺前体细胞。该模型为研究hFL - HCCs发病机制和潜在治疗方法提供了前所未有的机会。
