Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC.
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The data and code that support the findings of this study are available from the corresponding author on reasonable request. Source data for graphs showed in Figs. 4, 5 and Extended Data Figs. 1, 4–10 are available in the online version of this paper. Data from ChIP–seq experiments are available at the Sequence Read Archive (SRA) under the accession number SRP136997. Whole scans of western blots are depicted in Supplementary Fig. 1, and the gating strategy for flow cytometry is depicted in Supplementary Fig. 2.
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We thank E. Rist, P. Schiemann, C. Fellmeth, C.-J. Hsieh, D. Heide and J. Hetzer for technical help or assistance. We thank A. Weber for providing TLR2 and TLR4 knockout mice and W. S. Alexander and The Walter and Eliza Hall Institute of Medical Research for providing Mlklfl/fl mice. The Cas9n–p19Arf sgRNA vector was provided by W. Xue. We thank the c.ATG facility of Tuebingen University and CeGaT Tuebingen for exome sequencing and data analysis. This work was supported by the ERC Consolidator Grant ‘CholangioConcept’ (to L.Z.), the German Research Foundation (DFG): grants FOR2314, SFB685, SFB/TR209 and the Gottfried Wilhelm Leibniz Program (to L.Z.). Further funding was provided by the German Ministry for Education and Research (BMBF) (e:Med/Multiscale HCC), the German Universities Excellence Initiative (third funding line: ‘future concept’), the German Center for Translational Cancer Research (DKTK), the German-Israeli Cooperation in Cancer Research (DKFZ-MOST) (to L.Z.) and the Intramural Research Program of the Centre for Cancer Research, National Cancer Institute, National Institutes of Health (to X.W.W.). The group of O.B. is supported by grants from ANR-BMFT, Fondation ARC pour la recherche sur le Cancer, INSERM, and the National Cancer Institute of the National Institutes of Health under Award Number R01CA136533. O.B. is a CNRS fellow.
Nature thanks E. Guccione, E. Pikarsky and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
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