Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer

Intratumor heterogeneity may result from the evolution of tumor cells and their continuous interactions with the tumor microenvironment which collectively drives tumorigenesis. However, an appearance of cellular and molecular heterogeneity creates a challenge to define molecular features linked to tumormalignancy. Here we performmultiregional single-cell RNA sequencing (scRNA-seq) analysis of seven liver cancer patients (four hepatocellular carcinoma, HCC and three intrahepatic cholangiocarcinoma, iCCA). We identify cellular dynamics of malignant cells and their communication networks with tumor-associated immune cells, which are validated using additional scRNAseq data of 25 HCC and 12 iCCA patients as a stable fingerprint embedded in a malignant ecosystem representing features of tumor aggressiveness. We further validate the top ligand-receptor interaction pairs (i.e., LGALS9-SLC1A5 and SPP1-PTGER4 between tumor cells and macrophages) associated with unique transcriptome in additional 542 HCC patients. Our study unveils stable molecular networks of malignant ecosystems, which may open a path for therapeutic exploration.

Automated summary

Intratumor heterogeneity arises from the evolution of tumor cells and their interactions with the tumor microenvironment. This study uses single-cell RNA sequencing to analyze liver cancer patients, identifying cellular dynamics and communication networks between malignant cells and tumor-associated immune cells. The findings validate the stable molecular networks of malignant ecosystems and potentially open up new therapeutic opportunities.