The Tumor Microenvironment Drives Liver Cancer Lineage Commitment

Chronic liver inflammation and liver cirrhosis increase the risk of developing two distinct types of liver cancer, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). HCC and ICC have distinct morphologies and metastatic potentials, but both have been suggested to arise from hepatocytes, which have a high degree of cellular plasticity. However, the mechanism by which transformed hepatocytes commit to an HCC or ICC lineage has not been determined. To investigate liver tumorigenesis, Seehawer and colleagues used mosaic mouse models of liver cancer. Hydrodynamic tail-vein (HDTV) injection of transposable elements to promote hepatic delivery of the oncogenes Myc and NRAS^G12V or Myc and Akt1 induced HCC. In contrast, in vivo electroporation of the same oncogenes induced ICC or combined ICC–HCC. In vivo lineage tracing revealed that both HCC and ICC arise from differentiated hepatocytes, and the mutational profiles of HCC and ICC were similar. Mechanistically, HDTV primarily induced apoptosis, whereas electroporation predominantly induced necroptosis. The necroptotic-associated cytokine microenvironment induced by electroporation resulted in the development of ICC. In the absence of the necroptotic microenvironment, the same oncogenes induced HCC development instead of ICC development. Chromatin accessibility profiling via assay for transposase-accessible chromatin using sequencing (ATAC-seq) revealed that Tbx3 locus, which encodes a transcription factor involved in carcinogenesis, was accessible in HCC but inaccessible in ICC, resulting in increased expression of Tbx3 in HCC. Conversely, the transcription factor Prdm5 was accessible and highly expressed in ICC compared with HCC, indicating that TBX3 and PRDM5 may be essential regulators of lineage commitment in liver cancer. Collectively, these findings reveal that the microenvironment can regulate lineage commitment in liver cancer, with hepatocytes giving rise to ICC in a necroptotic microenvironment and HCC in an apoptotic microenvironment, even when the driver mutations are identical.

Seehawer M, Heinzmann F, D'Artista L, Harbig J, Roux PF, Hoenicke L, et al. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 2018;562:69–75.

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