%0 Journal Article %A Frank Jühling %A Antonio Saviano %A Clara Ponsolles %A Laura Heydmann %A Emilie Crouchet %A Sarah C Durand %A Houssein El Saghire %A Emanuele Felli %A Véronique Lindner %A Patrick Pessaux %A Nathalie Pochet %A Catherine Schuster %A Eloi R Verrier %A Thomas F Baumert %T Hepatitis B virus compartmentalization and single-cell differentiation in hepatocellular carcinoma %D 2021 %R 10.26508/lsa.202101036 %J Life Science Alliance %P e202101036 %V 4 %N 9 %X Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) world-wide. The molecular mechanisms of viral hepatocarcinogenesis are still partially understood. Here, we applied two complementary single-cell RNA-sequencing protocols to investigate HBV–HCC host cell interactions at the single cell level of patient-derived HCC. Computational analyses revealed a marked HCC heterogeneity with a robust and significant correlation between HBV reads and cancer cell differentiation. Viral reads significantly correlated with the expression of HBV-dependency factors such as HLF in different tumor compartments. Analyses of virus-induced host responses identified previously undiscovered pathways mediating viral carcinogenesis, such as E2F- and MYC targets as well as adipogenesis. Mapping of fused HBV–host cell transcripts allowed the characterization of integration sites in individual cancer cells. Collectively, single-cell RNA-Seq unravels heterogeneity and compartmentalization of both, virus and cancer identifying new candidate pathways for viral hepatocarcinogenesis. The perturbation of pro-carcinogenic gene expression even at low HBV levels highlights the need of HBV cure to eliminate HCC risk. %U https://www.life-science-alliance.org/content/lsa/4/9/e202101036.full.pdf