Necroptosis microenvironment directs lineage commitment in liver cancer

Marco Seehawer, Florian Heinzmann, Luana D’Artista, Jule Harbig, Pierre-François Roux, Lisa Hoenicke, Hien Dang, Sabrina Klotz, Lucas Robinson, Grégory Doré, Nir Rozenblum, Tae-Won Kang, Rishabh Chawla, Thorsten Buch, Mihael Vucur, Mareike Roth, Johannes Zuber, Tom Luedde, Bence Sipos, Thomas Longerich, Mathias Heikenwälder, Xin Wei Wang, Oliver Bischof and Lars Zender ()
Additional contact information
Marco Seehawer: University Hospital Tuebingen
Florian Heinzmann: University Hospital Tuebingen
Luana D’Artista: University Hospital Tuebingen
Jule Harbig: University Hospital Tuebingen
Pierre-François Roux: Institut Pasteur, Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection
Lisa Hoenicke: University Hospital Tuebingen
Hien Dang: Center for Cancer Research, National Cancer Institute
Sabrina Klotz: University Hospital Tuebingen
Lucas Robinson: Institut Pasteur, Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection
Grégory Doré: Institut Pasteur, Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection
Nir Rozenblum: Institut Pasteur, Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection
Tae-Won Kang: University Hospital Tuebingen
Rishabh Chawla: University Hospital Tuebingen
Thorsten Buch: Institute of Laboratory Animal Science University of Zurich, University of Zurich
Mihael Vucur: RWTH University Hospital Aachen, Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III)
Mareike Roth: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC)
Johannes Zuber: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC)
Tom Luedde: RWTH University Hospital Aachen, Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III)
Bence Sipos: University of Tuebingen
Thomas Longerich: University Hospital Heidelberg
Mathias Heikenwälder: German Cancer Research Center (DKFZ)
Xin Wei Wang: Center for Cancer Research, National Cancer Institute
Oliver Bischof: Institut Pasteur, Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection
Lars Zender: University Hospital Tuebingen

Nature, 2018, vol. 562, issue 7725, 69-75

Abstract: 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.

Keywords: Lineage Commitment; Necroptosis; Hepatic Microenvironment; Intrahepatic Cholangiocarcinoma (ICC); Hydrodynamic Tail Vein (HDTV) (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (3)

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DOI: 10.1038/s41586-018-0519-y

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