Journal Article

Necroptosis microenvironment directs lineage commitment in liver cancer

Klotz, Sabrina, Wang, Xin Wei, Harbig, Jule, Sipos, Bence, Longerich, Thomas, Doré, Grégory, Zuber, Johannes, Buch, Thorsten, Rozenblum, Nir, Zender, Lars, Robinson, Lucas, Heikenwälder, Mathias, Heinzmann, Florian, Roth, Mareike, Hoenicke, Lisa, Roux, Pierre-François, Seehawer, Marco, Dang, Hien, Vucur, Mihael, Bischof, Oliver, Luedde, Tom, D’Artista, Luana, Kang, Tae-Won, Chawla, Rishabh

2018

Overview

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. The tumour microenvironment determines which type of liver cancer develops, with transformed hepatocytes giving rise to intrahepatic cholangiocarcinoma or hepatocellular carcinoma depending or whether they are surrounded by cells undergoing necroptosis or apoptosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/2 / 13/31 / 13/44 / 13/51 / 13/89 / 45/15 / 45/61 / 631/67/327 / 631/67/68/2486 / 64/60 / 96/63 / Analysis / Animal models / Animals / Apoptosis / Apoptosis - genetics / B cells / Biliary tract cancer / Bioinformatics / Cancer / Cancer metastasis / Cancer research / Carcinogenesis / Carcinogenesis - genetics / Carcinoma / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - pathology / Cell Differentiation / Cell Lineage - genetics / Cholangiocarcinoma / Cholangiocarcinoma - genetics / Cholangiocarcinoma - pathology / Criminal investigation / Cyclin-Dependent Kinase Inhibitor p16 - deficiency / Cytokines / Cytokines - metabolism / Deoxyribonucleic acid / Development and progression / Disease Models, Animal / DNA / DNA methylation / DNA Transposable Elements - genetics / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Epigenesis, Genetic - genetics / Female / Gene expression / Gene Expression Profiling / Genes, myc / Genes, ras / Genomes / Health / Hepatocellular carcinoma / Hepatocytes / Hepatocytes - metabolism / Hepatocytes - pathology / Humanities and Social Sciences / Humans / Life Sciences / Liver / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - pathology / Male / Metastases / Metastasis / Mice / Morphology / Mosaicism / Motor vehicle drivers / multidisciplinary / Necroptosis / Necrosis - genetics / Proto-Oncogene Proteins c-akt - genetics / Risk analysis / Risk factors / Science / Science (multidisciplinary) / T-Box Domain Proteins - genetics / T-Box Domain Proteins - metabolism / Transcription Factors - genetics / Transcription Factors - metabolism / Tumor Microenvironment / Tumorigenesis / Tumors