Proteomic Landscape of Cholangiocarcinomas Reveals Three Different Subgroups According to Their Localization and the Aspect of Non-Tumor Liver

Abstract

Purpose: Cholangiocarcinomas (CCs) define a heterogeneous entity based upon their anatomic localization (intra versus extrahepatic) and, for the intrahepatic CCs, the aspect of background liver (normal versus cirrhosis). The aim of the study was to characterize the molecular heterogeneity of CCs by a global proteomic approach.

Experimental design: Thirty-three tumor samples from 17 intrahepatic CCs (iCC) (9 developed on normal (iCC_N ) and 8 developed in cirrhotic liver (iCC_C )); 5 hilar CCs (CC_H ); 5 pancreatic CCs (CC_P ) and 6 hepatocellular carcinomas (HCC), were submitted to label-free quantitative proteomic analysis. Differential proteins were analyzed by immunohistochemistry in a validation set of 30 CCs.

Results: Unsupervised analysis revealed two main clusters: cluster 1 contained most of the iCC_C while cluster 2 was divided in 2 subgroups, one containing most of the iCC_N and the other regrouping CC_H and CC_P . Compared to iCC_N , iCC_C displayed upregulation of molecules involved in cell adhesion, motility and angiogenesis. Epithelial markers associated with secretory pathway and fibroblast markers were overexpressed in CC_H compared to iCC_N CONCLUSION AND CLINICAL RELEVANCE: This study demonstrated that iCC_C is a specific entity, suggesting a major impact of the background liver on tumor biology, and confirmed that extrahepatic CCs define a homogeneous subgroup.

Keywords: cholangiocarcinoma; cirrhosis; label-free quantitative proteomics; tissue; tumor heterogeneity.