A Mouse Model of Cholangiocarcinoma Uncovers a Role for Tensin-4 in Tumor Progression
Mickaël Di-Luoffo
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorSophie Pirenne
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Department of Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
These authors contributed equally to this work.Search for more papers by this authorThoueiba Saandi
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
These authors contributed equally to this work.Search for more papers by this authorAxelle Loriot
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
These authors contributed equally to this work.Search for more papers by this authorClaude Gérard
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorNicolas Dauguet
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
CYTF Platform, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorFátima Manzano-Núñez
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorNatália Alves Souza Carvalhais
VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium
Search for more papers by this authorFlorence Lamoline
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorSabine Cordi
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorKatarzyna Konobrocka
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorVitaline De Greef
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorMina Komuta
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorGeorg Halder
VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium
Search for more papers by this authorPatrick Jacquemin
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorCorresponding Author
Frédéric P. Lemaigre
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Frédéric P. Lemaigre, M.D., Ph.D.
de Duve Institute, Université catholique de Louvain
Avenue Hippocrate 75/B1-7503
B-1200 Brussels, Belgium
E-mail: [email protected]
Tel.: +32 2 764 7583
Search for more papers by this authorMickaël Di-Luoffo
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorSophie Pirenne
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Department of Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
These authors contributed equally to this work.Search for more papers by this authorThoueiba Saandi
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
These authors contributed equally to this work.Search for more papers by this authorAxelle Loriot
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
These authors contributed equally to this work.Search for more papers by this authorClaude Gérard
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorNicolas Dauguet
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
CYTF Platform, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorFátima Manzano-Núñez
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorNatália Alves Souza Carvalhais
VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium
Search for more papers by this authorFlorence Lamoline
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorSabine Cordi
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorKatarzyna Konobrocka
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorVitaline De Greef
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorMina Komuta
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorGeorg Halder
VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium
Search for more papers by this authorPatrick Jacquemin
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Search for more papers by this authorCorresponding Author
Frédéric P. Lemaigre
de Duve Institute, Université catholique de Louvain, Brussels, Belgium
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Frédéric P. Lemaigre, M.D., Ph.D.
de Duve Institute, Université catholique de Louvain
Avenue Hippocrate 75/B1-7503
B-1200 Brussels, Belgium
E-mail: [email protected]
Tel.: +32 2 764 7583
Search for more papers by this authorAbstract
Background and Aims
Earlier diagnosis and treatment of intrahepatic cholangiocarcinoma (iCCA) are necessary to improve therapy, yet limited information is available about initiation and evolution of iCCA precursor lesions. Therefore, there is a need to identify mechanisms driving formation of precancerous lesions and their progression toward invasive tumors using experimental models that faithfully recapitulate human tumorigenesis.
Approach and Results
To this end, we generated a mouse model which combines cholangiocyte-specific expression of KrasG12D with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced inflammation to mimic iCCA development in patients with cholangitis. Histological and transcriptomic analyses of the mouse precursor lesions and iCCA were performed and compared with human analyses. The function of genes overexpressed during tumorigenesis was investigated in human cell lines. We found that mice expressing KrasG12D in cholangiocytes and fed a DDC diet developed cholangitis, ductular proliferations, intraductal papillary neoplasms of bile ducts (IPNBs), and, eventually, iCCAs. The histology of mouse and human IPNBs was similar, and mouse iCCAs displayed histological characteristics of human mucin-producing, large-duct–type iCCA. Signaling pathways activated in human iCCA were also activated in mice. The identification of transition zones between IPNB and iCCA on tissue sections, combined with RNA-sequencing analyses of the lesions supported that iCCAs derive from IPNBs. We further provide evidence that tensin-4 (TNS4), which is stimulated by KRASG12D and SRY-related HMG box transcription factor 17, promotes tumor progression.
Conclusions
We developed a mouse model that faithfully recapitulates human iCCA tumorigenesis and identified a gene cascade which involves TNS4 and promotes tumor progression.
Supporting Information
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| hep31834-sup-0001-Supinfo.pdfPDF document, 3.2 MB | Supplementary Material |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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Author names in bold designate shared co-first authorship.
