Transcriptomic signature of hepatocellular carcinoma and intrahepatic cholangiocarcinoma derived from oncogenically transformed murine hepatocytes after stable knock-down of Tbx3 or Prdm5

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 therapy response. Yet, molecular actors and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here, we report that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumourigenesis. While a necroptosis associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes harbouring identical oncogenic drivers give rise to HCC if surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of murine HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage commitment factors, a function conserved in humans. Together, our study provides unprecedented insights into lineage commitment in liver tumourigenesis and explains molecularly why common liver damaging risk factors can either lead to HCC or ICC.

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Seehawer M, Heinzmann F, D'Artista L, Harbig J, Roux PF, Hoenicke L, Dang H, Klotz S, Robinson L, Doré G, Rozenblum N, Kang TW, Chawla R, Buch T, Vucur M, Roth M, Zuber J, Luedde T, Sipos B, Longerich T, Heikenwälder M, Wang XW, Bischof O, Zender L