Necroptosis microenvironment directs lineage commitment in liver cancer

Marco Seehawer (1, 2) , Florian Heinzmann (1, 2) , Luana D’artista (1, 2) , Jule Harbig (1, 2) , Pierre-François Roux (3, 4) , Lisa Hoenicke (1, 2) , Hien Dang (5) , Sabrina Klotz (1, 2) , Lucas Robinson (3, 4) , Grégory Doré (3, 4) , Nir Rozenblum , Tae-Won Kang (1, 2) , Rishabh Chawla (1, 2) , Thorsten Buch (6) , Mihael Vucur (7) , Mareike Roth (8) , Johannes Zuber (8) , Tom Luedde (7) , Bence Sipos , Thomas Longerich (9, 10) , Mathias Heikenwalder (11) , Xin Wei Wang (5) , Oliver Bischof (3, 4) , Lars Zender (1, 2, 12, 11)

1 Universitätsklinikum Tübingen - University Hospital of Tübingen
2 Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
3 Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis
4 Equipe labellisée Ligue contre le Cancer
5 NCI-NIH - National Cancer Institute [Bethesda]
6 UZH - Universität Zürich [Zürich] = University of Zurich
7 UKA - Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany]
8 Vienna Biocenter - VBC [Austria]
9 University of Tübingen
10 Heidelberg University Hospital [Heidelberg]
11 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
12 DKTK - German Cancer Consortium [Heidelberg]

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.

Mots clés: Cancer epigenetics; Cancer microenvironment

Domaines: Cancer

Marco Seehawer, Florian Heinzmann, Luana D’artista, Jule Harbig, Pierre-François Roux, et al.. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature, 2018, 562 (7725), pp.69-75. ⟨10.1038/s41586-018-0519-y⟩. ⟨hal-02348982⟩