Necroptosis microenvironment directs lineage commitment in liver cancer
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 t...
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| Veröffentlicht in: | Nature (London) 2018-10, Vol.562 (7725), p.69-75 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1038/s41586-018-0519-y |
| format | Article |
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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.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-018-0519-y</identifier><identifier>PMID: 30209397</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><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</subject><ispartof>Nature (London), 2018-10, Vol.562 (7725), p.69-75</ispartof><rights>Springer Nature Limited 2018</rights><rights>COPYRIGHT 2018 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Oct 4, 2018</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c773t-cf9b673b64a846aeb92586ba6b04c7eab47c35678eee9dcfd486a6749f0c127f3</citedby><cites>FETCH-LOGICAL-c773t-cf9b673b64a846aeb92586ba6b04c7eab47c35678eee9dcfd486a6749f0c127f3</cites><orcidid>0000-0003-2422-6277</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-018-0519-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-018-0519-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30209397$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02348982$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Seehawer, Marco</creatorcontrib><creatorcontrib>Heinzmann, Florian</creatorcontrib><creatorcontrib>D’Artista, Luana</creatorcontrib><creatorcontrib>Harbig, Jule</creatorcontrib><creatorcontrib>Roux, Pierre-François</creatorcontrib><creatorcontrib>Hoenicke, Lisa</creatorcontrib><creatorcontrib>Dang, Hien</creatorcontrib><creatorcontrib>Klotz, Sabrina</creatorcontrib><creatorcontrib>Robinson, Lucas</creatorcontrib><creatorcontrib>Doré, Grégory</creatorcontrib><creatorcontrib>Rozenblum, Nir</creatorcontrib><creatorcontrib>Kang, Tae-Won</creatorcontrib><creatorcontrib>Chawla, Rishabh</creatorcontrib><creatorcontrib>Buch, Thorsten</creatorcontrib><creatorcontrib>Vucur, Mihael</creatorcontrib><creatorcontrib>Roth, Mareike</creatorcontrib><creatorcontrib>Zuber, Johannes</creatorcontrib><creatorcontrib>Luedde, Tom</creatorcontrib><creatorcontrib>Sipos, Bence</creatorcontrib><creatorcontrib>Longerich, Thomas</creatorcontrib><creatorcontrib>Heikenwälder, Mathias</creatorcontrib><creatorcontrib>Wang, Xin Wei</creatorcontrib><creatorcontrib>Bischof, Oliver</creatorcontrib><creatorcontrib>Zender, Lars</creatorcontrib><title>Necroptosis microenvironment directs lineage commitment in liver cancer</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>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.</description><subject>13/2</subject><subject>13/31</subject><subject>13/44</subject><subject>13/51</subject><subject>13/89</subject><subject>45/15</subject><subject>45/61</subject><subject>631/67/327</subject><subject>631/67/68/2486</subject><subject>64/60</subject><subject>96/63</subject><subject>Analysis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - genetics</subject><subject>B cells</subject><subject>Biliary tract cancer</subject><subject>Bioinformatics</subject><subject>Cancer</subject><subject>Cancer metastasis</subject><subject>Cancer research</subject><subject>Carcinogenesis</subject><subject>Carcinogenesis - genetics</subject><subject>Carcinoma</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Differentiation</subject><subject>Cell Lineage - genetics</subject><subject>Cholangiocarcinoma</subject><subject>Cholangiocarcinoma - genetics</subject><subject>Cholangiocarcinoma - pathology</subject><subject>Criminal investigation</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - deficiency</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Deoxyribonucleic acid</subject><subject>Development and progression</subject><subject>Disease Models, Animal</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA Transposable Elements - genetics</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Epigenesis, Genetic - genetics</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Genes, myc</subject><subject>Genes, ras</subject><subject>Genomes</subject><subject>Health</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatocytes</subject><subject>Hepatocytes - metabolism</subject><subject>Hepatocytes - pathology</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Liver</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - pathology</subject><subject>Male</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Morphology</subject><subject>Mosaicism</subject><subject>Motor vehicle drivers</subject><subject>multidisciplinary</subject><subject>Necroptosis</subject><subject>Necrosis - genetics</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Risk analysis</subject><subject>Risk factors</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>T-Box Domain Proteins - genetics</subject><subject>T-Box Domain Proteins - metabolism</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Tumor Microenvironment</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kk1vEzEQhleIiobCD-CCVvTUwxZ77fjjghRV0FaKQOLjbHm9s1tXWTu1NxH590xIv4KCfLA188w7Y_stineUnFPC1MfM6VSJilBVkSnV1eZFMaFciooLJV8WE0JqzCgmjovXOd8SgpTkr4pjRmqimZaT4vIruBSXY8w-l4PHM4S1TzEMEMay9QncmMuFD2B7KF0cBj_-TfmA0TWk0tngIL0pjjq7yPD2fj8pfn35_PPiqpp_u7y-mM0rJyUbK9fpRkjWCG4VFxYaXeMNGisawp0E23Dp2FRIBQC6dV3LlbBCct0RR2vZsZPi0053uWoGaB2OkuzCLJMfbNqYaL3ZzwR_Y_q4NopSKjVBgbOdwM0_ZVezudnGSM240qpeU2RP75uleLeCPJrbuEoB72dqWjNBKSPyiertAowPXcTGbvDZmdlU1loLphlS1QGqhwA4ZQzQeQzv8R8O8G7p78xz6PwAhKsF_MuDqmd7BciM8Hvs7Spnc_3j-z5LdyyaIucE3eNzUWK2_jM7_xn0n9n6z2yw5v3z73mseDAcAvUOyJgKPaSnJ_2_6h8k-OPv</recordid><startdate>201810</startdate><enddate>201810</enddate><creator>Seehawer, 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microenvironment directs lineage commitment in liver cancer</title><author>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, 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Database</collection><collection>Earth, Atmospheric & Aquatic Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>University of Michigan</collection><collection>Genetics Abstracts</collection><collection>SIRS Editorial</collection><collection>Environment Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Seehawer, Marco</au><au>Heinzmann, Florian</au><au>D’Artista, Luana</au><au>Harbig, Jule</au><au>Roux, Pierre-François</au><au>Hoenicke, Lisa</au><au>Dang, Hien</au><au>Klotz, Sabrina</au><au>Robinson, Lucas</au><au>Doré, Grégory</au><au>Rozenblum, Nir</au><au>Kang, Tae-Won</au><au>Chawla, Rishabh</au><au>Buch, Thorsten</au><au>Vucur, Mihael</au><au>Roth, Mareike</au><au>Zuber, Johannes</au><au>Luedde, Tom</au><au>Sipos, Bence</au><au>Longerich, Thomas</au><au>Heikenwälder, Mathias</au><au>Wang, Xin Wei</au><au>Bischof, Oliver</au><au>Zender, Lars</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Necroptosis microenvironment directs lineage commitment in liver cancer</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2018-10</date><risdate>2018</risdate><volume>562</volume><issue>7725</issue><spage>69</spage><epage>75</epage><pages>69-75</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><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.
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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30209397</pmid><doi>10.1038/s41586-018-0519-y</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0003-2422-6277</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2018-10, Vol.562 (7725), p.69-75 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8111790 |
| source | MEDLINE; SpringerLink Journals; Nature |
| subjects | 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 |
| title | Necroptosis microenvironment directs lineage commitment in liver cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T02%3A57%3A46IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Necroptosis%20microenvironment%20directs%20lineage%20commitment%20in%20liver%20cancer&rft.jtitle=Nature%20(London)&rft.au=Seehawer,%20Marco&rft.date=2018-10&rft.volume=562&rft.issue=7725&rft.spage=69&rft.epage=75&rft.pages=69-75&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-018-0519-y&rft_dat=%3Cgale_pubme%3EA572996393%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2123611307&rft_id=info:pmid/30209397&rft_galeid=A572996393&rfr_iscdi=true |