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Necroptosis microenvironment directs lineage commitment in liver cancer

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

Nature (London), 2018-10, Vol.562 (7725), p.69-75 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Necroptosis microenvironment directs lineage commitment in liver cancer
Autor: Seehawer, Marco ; Heinzmann, Florian ; D'Artista, Luana ; Harbig, Jule ; Roux, Pierre-François ; Hoenicke, Lisa ; Dang, Hien ; Klotz, Sabrina ; Robinson, Lucas ; Doré, Grégory ; Rozenblum, Nir ; Kang, Tae-Won ; Chawla, Rishabh ; Buch, Thorsten ; Vucur, Mihael ; Roth, Mareike ; Zuber, Johannes ; Luedde, Tom ; Sipos, Bence ; Longerich, Thomas ; Heikenwälder, Mathias ; Wang, Xin Wei ; Bischof, Oliver ; Zender, Lars
Assuntos: 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 ; Humans ; Life Sciences ; Liver ; Liver cancer ; Liver Neoplasms - genetics ; Liver Neoplasms - pathology ; Male ; Metastases ; Metastasis ; Mice ; Morphology ; Mosaicism ; Motor vehicle drivers ; Necroptosis ; Necrosis - genetics ; Oncology, Experimental ; Proto-Oncogene Proteins c-akt - genetics ; Risk analysis ; Risk factors ; T-Box Domain Proteins - genetics ; T-Box Domain Proteins - metabolism ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Tumor Microenvironment ; Tumorigenesis ; Tumors
É parte de: Nature (London), 2018-10, Vol.562 (7725), p.69-75
Notas: Author contributions The study was designed by L.Z., M.S. and F.H with support from O.B. T.B. provided TLR KO (TLR2, 3, 4, 7 and 9 KO) mice. Mouse experiments, western blots, qRT–PCR, immunohistochemistry, immunofluorescence, vector generation and cell culture work were conducted and analysed by M.S., F.H. and L.Z. L.D. performed and analysed flow cytometry experiments, J.H. performed immunohistochemistry, immunofluorescence and mouse sampling, L.H. crossed ROSAmT/mG × Alb-cre × p19Arf−/− mice, S.K. and T.-W.K. conducted mouse experiments, R.C. subcloned vectors and performed knockdown experiments. Histopathological analyses were performed by T.Lo. and B.S. Human ICC and HCC samples were collected and analysed by H.D. and X.W.W. ChIP–seq, ATAC-seq, transcriptome and integrative analyses were performed by P.-F.R., O.B., G.D., N.R., L.R., M.R., J.Z. and M.H. M.V. and T.Lu. generated the Alb-cre × Mlklfl/fl mice and conducted MLKL western blot analyses. L.Z. supervised the overall execution of experiments and analysed data. The manuscript was written by L.Z. with support from, M.S., F.H. and O.B.
Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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Necroptosis microenvironment directs lineage commitment in liver cancer

England: Nature Publishing Group

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