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A Mouse Model of Cholangiocarcinoma Uncovers a Role for Tensin‐4 in Tumor Progression
Author(s) -
DiLuoffo Mickaël,
Pirenne Sophie,
Saandi Thoueiba,
Loriot Axelle,
Gérard Claude,
Dauguet Nicolas,
ManzanoNúñez Fátima,
Alves Souza Carvalhais Natália,
Lamoline Florence,
Cordi Sabine,
Konobrocka Katarzyna,
De Greef Vitaline,
Komuta Mina,
Halder Georg,
Jacquemin Patrick,
Lemaigre Frédéric P.
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31834
Subject(s) - carcinogenesis , cancer research , biology , tumor progression , mucin 2 , tensin , pathology , transcriptome , gene , medicine , gene expression , pten , signal transduction , microbiology and biotechnology , genetics , pi3k/akt/mtor pathway
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 Kras G12D 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 Kras G12D 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 KRAS G12D 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.