A single-cell atlas of hepatocellular carcinoma.

46 Background: Tumors reside and evolve in a complex ecosystem of immune and non-immune stromal cells. Methods: We employed multi-sectoral single-cell RNA-seq to catalogue intra-tumor heterogeneity in human hepatocellular carcinoma (HCC). Results: We generated single-cell atlas of ~76,000 cells from fourteen HCC patients, each consisting of 2-5 tumor and matched adjacent normal sectors. In total, we profiled 57 individual tumor and normal sectors consisting of HBV+ and HBV- HCC. By analysing matched normal and malignant sectors we observed intriguing remodelling of the tumor microenvironment (TME).We identify >70 distinct cells-states in HCC including novel, previously uncharacterized subpopulations. Specifically, we demonstrate remarkable heterogeneity in hepatocytes, fibroblast and endothelial cells. Most importantly, we consistently observed a marked remodellingof stromal cells suggesting a role in dynamic tumor-TME interactions. Conclusions: We present the first comprehensive single-cell atlas of HCC. This resource provides unprecedented insights into liver cancer, which will pave the way for early detection and therapeutic targeting.