Necroptosis microenvironment directs lineage commitment in liver cancer
Open accessAbstract
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.
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Hepatocytes can give rise to both HCC and CCA.
“Indeed, hepatocytes can give rise to both HCC and CCA18, and our data suggest that PROX1 regulates this decision.”
From Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis (2025) · cites this paper as [18]
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- Authors
- Seehawer, M., Heinzmann, F., D’Artista, L., Harbig, J., Roux, P.-F., Hoenicke, L., Dang, H., Klotz, S., Robinson, L., Doré, G., Rozenblum, N., Kang, T.-W., Chawla, R., Buch, T., Vucur, M., Roth, M., Zuber, J., Luedde, T., Sipos, B., Longerich, T., Heikenwälder, M., Wang, X. W., Bischof, O., & Zender, L.
- Affiliations
- Universitätsklinikum Tübingen (DE)
- Inserm (FR)
- National Cancer Institute (US)
- Institut Pasteur (FR)
- University of Zurich (CH)
- Universitätsklinikum Aachen (DE)
- Research Institute of Molecular Pathology (AT)
- University of Tübingen (DE)
- University Hospital Heidelberg (DE)
- German Cancer Research Center (DE)
- Corresponding author
- Zender, Lars
- ORCID
- Venue
- Nature
- Published
- 2018-09-12
- Volume
- 562
- Issue
- 7725
- Pages
- 69-75
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8111790
- OpenAlex
- W2890271012
- Cited by
- 406
- References
- 47
- Citations by year
- 2026: 11 · 2025: 43 · 2024: 40 · 2023: 82 · 2022: 83 · 2021: 60 · 2020: 39 · 2019: 43 · 2018: 5
- FWCI
- 23.03
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-11-08)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (Z01BC010313, R01CA136533)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- necroptosis, tumor microenvironment, lineage commitment, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, hepatocarcinogenesis, epigenetic regulation, TBX3, PRDM5, apoptosis, hepatocyte transformation, cytokine microenvironment
- MeSH terms
- Animals, Cell Differentiation, Disease Models, Animal, DNA Transposable Elements, DNA-Binding Proteins, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Mosaicism, Necrosis, Genes, ras, Transcription Factors, Cytokines, Genes, myc, Apoptosis, Cholangiocarcinoma, Cell Lineage, Cyclin-Dependent Kinase Inhibitor p16, T-Box Domain Proteins, Gene Expression Profiling, Hepatocytes, Epigenesis, Genetic, Proto-Oncogene Proteins c-akt, Mice, Tumor Microenvironment, Carcinogenesis
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