| Literature DB >> 30209397 |
Marco Seehawer1,2, Florian Heinzmann1,2, Luana D'Artista1,2, Jule Harbig1,2, Pierre-François Roux3,4,5, Lisa Hoenicke1,2, Hien Dang6, Sabrina Klotz1,2, Lucas Robinson3,4,5, Grégory Doré3,4,5, Nir Rozenblum3, Tae-Won Kang1,2, Rishabh Chawla1,2, Thorsten Buch7, Mihael Vucur8, Mareike Roth9, Johannes Zuber9, Tom Luedde8, Bence Sipos10, Thomas Longerich11, Mathias Heikenwälder12, Xin Wei Wang6, Oliver Bischof3,4,5, Lars Zender13,14,15.
Abstract
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.Entities:
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Year: 2018 PMID： 30209397 PMCID： PMC8111790 DOI： 10.1038/s41586-018-0519-y
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962