Single-cell transcriptome analysis identifies novel biomarkers involved in major liver cancer subtypes

Abstract

Abstract Background Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two aggressive subtypes of liver cancer (LC). Immense cellular heterogeneity and crosstalk between cancer and healthy cells make it challenging to treat these cancer subtypes. To address these challenges, the study aims to systematically characterize the tumour heterogeneity of LC subtypes using single-cell RNA sequencing (scRNA-seq) datasets. Method The study combined 51927 single cells from HCC, ICC, and healthy scRNA-seq datasets. After integrating the datasets, cell groups with similar gene expression patterns are clustered and cluster annotation has been performed based on gene markers. Cell-cell communication analysis (CCA) was implemented to understand the crosstalk between various cell types. Further, differential gene expression analysis and enrichment analysis were carried out to identify unique molecular drivers associated with HCC and ICC. Results Our analysis identified T-cells, hepatocytes, epithelial cells, and monocyte are the major cell types present in the tumour microenvironment. Among them, abundance of natural killer (NK) cells in HCC, epithelial cells and hepatocytes in ICC were detected. CCA revealed key interaction between T-cells to NK cells in HCC and smooth muscle cells to epithelial cells in the ICC. Additionally, SOX4 and DTHD1 are the top differentially expressed genes (DEGs) in HCC, while keratin and CCL4 are in ICC. Enrichment analysis of DEGs reveals major up-regulated genes in HCC affect protein folding mechanism and in ICC alter pathways involved in cell adhesion. Conclusion The findings suggest potential targets for the development of novel therapeutic strategies for the treatment of these two aggressive subtypes of LC.