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Necroptosis microenvironment directs lineage commitment in liver cancer

Author

Listed:
  • Marco Seehawer

    (University Hospital Tuebingen
    Institute of Physiology, Eberhard Karls University Tuebingen)

  • Florian Heinzmann

    (University Hospital Tuebingen
    Institute of Physiology, Eberhard Karls University Tuebingen)

  • Luana D’Artista

    (University Hospital Tuebingen
    Institute of Physiology, Eberhard Karls University Tuebingen)

  • Jule Harbig

    (University Hospital Tuebingen
    Institute of Physiology, Eberhard Karls University Tuebingen)

  • Pierre-François Roux

    (Institut Pasteur, Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection
    INSERM
    Equipe Labellisée Fondation ARC pour la recherche sur le cancer)

  • Lisa Hoenicke

    (University Hospital Tuebingen
    Institute of Physiology, Eberhard Karls University Tuebingen)

  • Hien Dang

    (Center for Cancer Research, National Cancer Institute)

  • Sabrina Klotz

    (University Hospital Tuebingen
    Institute of Physiology, Eberhard Karls University Tuebingen)

  • Lucas Robinson

    (Institut Pasteur, Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection
    INSERM
    Equipe Labellisée Fondation ARC pour la recherche sur le cancer)

  • Grégory Doré

    (Institut Pasteur, Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection
    INSERM
    Equipe Labellisée Fondation ARC pour la recherche sur le cancer)

  • Nir Rozenblum

    (Institut Pasteur, Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection)

  • Tae-Won Kang

    (University Hospital Tuebingen
    Institute of Physiology, Eberhard Karls University Tuebingen)

  • Rishabh Chawla

    (University Hospital Tuebingen
    Institute of Physiology, Eberhard Karls University 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
    INSERM
    Equipe Labellisée Fondation ARC pour la recherche sur le cancer)

  • Lars Zender

    (University Hospital Tuebingen
    Institute of Physiology, Eberhard Karls University Tuebingen
    German Cancer Research Center (DKFZ))

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.

Suggested Citation

  • 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 & R, 2018. "Necroptosis microenvironment directs lineage commitment in liver cancer," Nature, Nature, vol. 562(7725), pages 69-75, October.
    • Handle: RePEc:nat:nature:v:562:y:2018:i:7725:d:10.1038_s41586-018-0519-y
    DOI: 10.1038/s41586-018-0519-y
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    Cited by:

    1. Ma. Teresa G. De Guzman, PhD, 2024. "Beyond the Policy: An Ethnographic Exploration of IKSP in Philippine Practice," International Journal of Research and Innovation in Social Science, International Journal of Research and Innovation in Social Science (IJRISS), vol. 8(7), pages 513-517, July.
    2. Jinhu Liu & Huajun Zhao & Tong Gao & Xinyan Huang & Shujun Liu & Meichen Liu & Weiwei Mu & Shuang Liang & Shunli Fu & Shijun Yuan & Qinglin Yang & Panpan Gu & Nan Li & Qingping Ma & Jie Liu & Xinke Zh, 2024. "Glypican-3-targeted macrophages delivering drug-loaded exosomes offer efficient cytotherapy in mouse models of solid tumours," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Panpan Tian & Wenwen Yang & Xiaowei Guo & Tixiao Wang & Siyu Tan & Renhui Sun & Rong Xiao & Yuzhen Wang & Deyan Jiao & Yachen Xu & Yanfei Wei & Zhuanchang Wu & Chunyang Li & Lifen Gao & Chunhong Ma & , 2023. "Early life gut microbiota sustains liver-resident natural killer cells maturation via the butyrate-IL-18 axis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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