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Necroptosis microenvironment directs lineage commitment in liver cancer


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.

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.

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Contributors:Rist, E, Weber, A, Xue, W, Hezter, J, Schiemann, P, Fellmeth, C, Hsieh, C-J, Heide, D, CeGaT Tuebingen, c.ATG facility of Tuebingen University
Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Laboratory Animal Science
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:1 October 2018
Deposited On:21 Nov 2018 14:47
Last Modified:22 Nov 2018 08:30
Publisher:Nature Publishing Group
ISSN:0028-0836
OA Status:Closed
Publisher DOI:https://doi.org/10.1038/s41586-018-0519-y
PubMed ID:30209397
Project Information:
  • : FunderERC Consolidator Grant ‘CholangioConcept’ (to L.Z.)
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  • : FunderGerman Research Foundation (DFG)
  • : Grant IDFOR2314, SFB685, SFB/TR209
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  • : FunderGottfried Wilhelm Leibniz Program (to L.Z.)
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  • : FunderGerman Ministry for Education and Research (BMBF)
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  • : Project Title(e:Med/Multiscale HCC)
  • : FunderGerman Universities Excellence Initiative (third funding line: ‘future concept’)
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  • : FunderGerman Center for Translational Cancer Research (DKTK)
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  • : FunderGerman-Israeli Cooperation in Cancer Research (DKFZ-MOST) (to L.Z.)
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  • : FunderIntramural Research Program of the Centre for Cancer Research, National Cancer Institute, National Institutes of Health (to X.W.W.)
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  • : FunderThe 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
  • : Grant IDR01CA136533
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  • : FunderO.B. is a CNRS fellow
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