Single-Cell Transcriptomic Analysis Reveals Two Molecularly and Clinically Distinct Subtypes of Intrahepatic Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous cancer with limited understanding of its classification and tumor microenvironment. Here, we performed single-cell RNA sequencing on 144,878 cells from 14 pairs of iCCA tumors and non-tumor liver tissues. We found that S100P and SPP1 are two reliable markers for iCCA perihilar large duct type (iCCAphl) and peripheral small duct type (iCCApps). S100P + SPP1- iCCAphl has significantly reduced levels of infiltrating CD3+ T cells, CD56+ NK cells, and increased CCL18+ macrophages compared to S100P-SPP1 + iCCApps. The transcriptor CREB3L1 is identified to regulate the S100P expression and promote tumor cell invasion. S100P-SPP1 + iCCApps has significantly more SPP1+ macrophage infiltration, less aggressiveness and better survival than S100P + SPP1- iCCAphl. Moreover, S100P-SPP1 + iCCApps harbors tumor cells at different status of differentiation, such as ALB + hepatocyte differentiation and ID3 + stemness. Our study extends our understanding of the diversity of tumor cells in iCCA and provides clearer understanding of iCCA classification.