Tumor progression in cholangiocarcinoma. Tumor progression in cholangiocarcinoma

Purpose: The aim of this study is to investigate mechanisms driving tumor-promoting mechanisms in cholangiocarcinoma while focusing on transitions from normal cholangiocytes to precancer lesions and from precancer lesion to invasive carcinoma. An original mouse model of intrahepatic cholangiocarcinoma was developed, based on induction of a KrasG12D mutation in cholangiocytes combined with chronic inflammation. RNA-Seq analyses compare the transcriptome of ductular proliferations, intraductal papillary neoplasm of the bile duct and intrahepatic cholangiocarcinoma. A gene cascade involving EGF, KrasG12D, Sox17 and Tns4 was identified to promote tumor progression. Overall design: Ductular proliferations (Duct Prol), intraductal papillary neoplasm of the bile duct (IPNB) and intrahepatic cholangiocarcinoma (iCCA) were laser-capture microdissected from livers of mice expressing KrasG12D and affected with diet-induced cholangitis (n=3 for all lesions in 3 independent mice). These samples were subjected to RNAseq analysis and compared with FACS-purified control cholangiocytes (CTL).