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

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

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.

Abstract

With no cell lines available, investigating the aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs) has proved problematic. Here, Oikawa et al. establish a model of hFL-HCCs as a transplantable tumour line maintained in immune-compromised mice, which proves rich in cancer stem cells.

Related collections

Most cited references 48

Record: found
Abstract: found
Article: not found

Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.

Cécile Guichard, Giuliana Amaddeo, Sandrine Imbeaud … (2012)

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Here, we performed high-resolution copy-number analysis on 125 HCC tumors and whole-exome sequencing on 24 of these tumors. We identified 135 homozygous deletions and 994 somatic mutations of genes with predicted functional consequences. We found new recurrent alterations in four genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses showed tumor suppressor properties for IRF2, whose inactivation, exclusively found in hepatitis B virus (HBV)-related tumors, led to impaired TP53 function. In contrast, inactivation of chromatin remodelers was frequent and predominant in alcohol-related tumors. Moreover, association of mutations in specific genes (RPS6KA3-AXIN1 and NFE2L2-CTNNB1) suggested that Wnt/β-catenin signaling might cooperate in liver carcinogenesis with both oxidative stress metabolism and Ras/mitogen-activated protein kinase (MAPK) pathways. This study provides insight into the somatic mutational landscape in HCC and identifies interactions between mutations in oncogene and tumor suppressor gene mutations related to specific risk factors.

0 comments Cited 578 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Dclk1 distinguishes between tumor and normal stem cells in the intestine.

Yoshiharu Sakai, Ryoichiro Kageyama, Mayumi Kawada … (2012)

There is great interest in tumor stem cells (TSCs) as potential therapeutic targets; however, cancer therapies targeting TSCs are limited. A drawback is that TSC markers are often shared by normal stem cells (NSCs); thus, therapies that target these markers may cause severe injury to normal tissues. To identify a potential TSC-specific marker, we focused on doublecortin-like kinase 1 (Dclk1). Dclk1 was reported as a candidate NSC marker in the gut, but recent reports have implicated it as a marker of differentiated cells (for example, Tuft cells). Using lineage-tracing experiments, we show here that Dclk1 does not mark NSCs in the intestine but instead marks TSCs that continuously produce tumor progeny in the polyps of Apc(Min/+) mice. Specific ablation of Dclk1-positive TSCs resulted in a marked regression of polyps without apparent damage to the normal intestine. Our data suggest the potential for developing a therapy for colorectal cancer based on targeting Dclk1-positive TSCs.

0 comments Cited 179 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma.

Joshua N. Honeyman, Elana P Simon, Nicolas Robine … (2014)

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis. We identified a chimeric transcript that is expressed in FL-HCC but not in adjacent normal liver and that arises as the result of a ~400-kilobase deletion on chromosome 19. The chimeric RNA is predicted to code for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity. Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the FL-HCCs examined (15/15) suggests that this genetic alteration contributes to tumor pathogenesis.

0 comments Cited 174 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Pub. Group

ISSN (Electronic): 2041-1723

Publication date (Electronic): 06 October 2015

Publication date Collection: 2015

Volume: 6

Electronic Location Identifier: 8070

Affiliations

[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

Author notes

[a ] praveen_sethupathy@ 123456med.unc.edu

[b ] Lola.M.Reid@ 123456gmail.com

[*]

These authors contributed equally to this work

[†]

These authors jointly supervised this work

Article

Publisher Item ID: ncomms9070

DOI: 10.1038/ncomms9070

PMC ID: 4600730

PubMed ID: 26437858

SO-VID: 999b674d-bfc2-496c-b14a-dc5a9b72b4cb

License:

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

History

Date received : 20 January 2015

Date accepted : 14 July 2015

Comments

Comment on this article

scite_

Cited by 39

See all cited by

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

Read this article at

Abstract

Abstract

Related collections

Stress signalling in stem cells

Most cited references 48

Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.

Dclk1 distinguishes between tumor and normal stem cells in the intestine.

Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma.

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 1,207

Cited by 39