Single-cell transcriptomic analysis suggests two molecularly distinct subtypes of intrahepatic cholangiocarcinoma (vol 12, 1642, 2022)

The molecular classification and tumour microenvironment in intrahepatic cholangiocarcinoma (iCCA) need further characterisation. Here, the authors perform single cell RNA-sequencing from 14 pairs of iCCA tumours and non-tumour liver tissues and propose S100P and SPP1 as markers for patient classification. Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous cancer with limited understanding of its classification and tumor microenvironment. Here, by performing single-cell RNA sequencing on 144,878 cells from 14 pairs of iCCA tumors and non-tumor liver tissues, we find that S100P and SPP1 are two markers for iCCA perihilar large duct type (iCCA(phl)) and peripheral small duct type (iCCA(pps)). S100P + SPP1- iCCA(phl) has significantly reduced levels of infiltrating CD4(+) T cells, CD56(+) NK cells, and increased CCL18(+) macrophages and PD1(+)CD8(+) T cells compared to S100P-SPP1 + iCCA(pps). The transcription factor CREB3L1 is identified to regulate the S100P expression and promote tumor cell invasion. S100P-SPP1 + iCCA(pps) has significantly more SPP1(+) macrophage infiltration, less aggressiveness and better survival than S100P + SPP1- iCCA(phl). Moreover, S100P-SPP1 + iCCA(pps) harbors tumor cells at different status of differentiation, such as ALB + hepatocyte differentiation and ID3+ stemness. Our study extends the understanding of the diversity of tumor cells in iCCA.