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Nature. 2018 Oct;562(7725):69-75. doi: 10.1038/s41586-018-0519-y. Epub 2018 Sep 12.

Necroptosis microenvironment directs lineage commitment in liver cancer.

Author information

1
Department of Internal Medicine VIII, University Hospital Tuebingen, Tuebingen, Germany.
2
Department of Physiology I, Institute of Physiology, Eberhard Karls University Tuebingen, Tuebingen, Germany.
3
Institut Pasteur, Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection, Paris, France.
4
INSERM, U993, Paris, France.
5
Equipe Labellisée Fondation ARC pour la recherche sur le cancer, Villejuif, France.
6
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
7
Institute of Laboratory Animal Science University of Zurich, University of Zurich, Schlieren, Switzerland.
8
RWTH University Hospital Aachen, Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), Aachen, Germany.
9
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
10
Institute of Pathology, University of Tuebingen, Tuebingen, Germany.
11
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
12
Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
13
Department of Internal Medicine VIII, University Hospital Tuebingen, Tuebingen, Germany. lars.zender@med.uni-tuebingen.de.
14
Department of Physiology I, Institute of Physiology, Eberhard Karls University Tuebingen, Tuebingen, Germany. lars.zender@med.uni-tuebingen.de.
15
Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. lars.zender@med.uni-tuebingen.de.

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.

PMID:
30209397
DOI:
10.1038/s41586-018-0519-y
[Indexed for MEDLINE]

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