Academic Journal
Hepatic zonation determines tumorigenic potential of mutant β-catenin.
| Τίτλος: | Hepatic zonation determines tumorigenic potential of mutant β-catenin. |
|---|---|
| Συγγραφείς: | Raven A; Cancer Research UK Scotland Institute, Glasgow, UK., Gilroy K; Cancer Research UK Scotland Institute, Glasgow, UK., Jin H; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA., Waldron JA; Cancer Research UK Scotland Institute, Glasgow, UK., Leslie H; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Munro J; Cancer Research UK Scotland Institute, Glasgow, UK., Hall H; Cancer Research UK Scotland Institute, Glasgow, UK., Ridgway RA; Cancer Research UK Scotland Institute, Glasgow, UK., Ford CA; Cancer Research UK Scotland Institute, Glasgow, UK., Gulhan DC; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA., Vlahov N; Cancer Research UK Scotland Institute, Glasgow, UK., Mills ML; Cancer Research UK Scotland Institute, Glasgow, UK., Hartley A; Cancer Research UK Scotland Institute, Glasgow, UK., Anderson E; Cancer Research UK Scotland Institute, Glasgow, UK., Bryson S; Cancer Research UK Scotland Institute, Glasgow, UK., Sphyris N; Cancer Research UK Scotland Institute, Glasgow, UK., Müller M; Cancer Research UK Scotland Institute, Glasgow, UK., May S; Cancer Research UK Scotland Institute, Glasgow, UK.; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Cadden B; Cancer Research UK Scotland Institute, Glasgow, UK., Nixon C; Cancer Research UK Scotland Institute, Glasgow, UK., Waddell SH; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., Guest R; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; CRUK Scotland Centre, Glasgow, UK., Boulter L; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; CRUK Scotland Centre, Glasgow, UK., Barker N; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Clevers H; Pharma, Research and Early Development (pRED) of F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, the Netherlands., Zhu H; Children's Research Institute and Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Ivaska J; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland., Strathdee D; Cancer Research UK Scotland Institute, Glasgow, UK., Miller CJ; Cancer Research UK Scotland Institute, Glasgow, UK.; School of Cancer Sciences, University of Glasgow, Glasgow, UK.; CRUK Scotland Centre, Glasgow, UK., Jamieson NB; School of Cancer Sciences, University of Glasgow, Glasgow, UK.; CRUK Scotland Centre, Glasgow, UK., Bushell M; Cancer Research UK Scotland Institute, Glasgow, UK.; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Park PJ; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA., Bird TG; Cancer Research UK Scotland Institute, Glasgow, UK.; School of Cancer Sciences, University of Glasgow, Glasgow, UK.; CRUK Scotland Centre, Glasgow, UK.; MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Sansom OJ; Cancer Research UK Scotland Institute, Glasgow, UK. o.sansom@crukscotlandinstitute.ac.uk.; School of Cancer Sciences, University of Glasgow, Glasgow, UK. o.sansom@crukscotlandinstitute.ac.uk.; CRUK Scotland Centre, Glasgow, UK. o.sansom@crukscotlandinstitute.ac.uk. |
| Πηγή: | Nature [Nature] 2026 Jan; Vol. 649 (8097), pp. 739-748. Date of Electronic Publication: 2025 Nov 19. |
| Τύπος έκδοσης: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
| Imprint Name(s): | Publication: Basingstoke : Nature Publishing Group Original Publication: London, Macmillan Journals ltd. |
| Ιατρικοί όροι (MeSH): | beta Catenin*/genetics , beta Catenin*/metabolism , Liver*/pathology , Liver*/metabolism , Liver*/cytology , Carcinogenesis*/genetics , Carcinogenesis*/pathology , Mutation*/genetics , Liver Neoplasms*/pathology , Liver Neoplasms*/genetics , Liver Neoplasms*/metabolism , Mutant Proteins*/metabolism , Mutant Proteins*/genetics, Hepatocytes/metabolism ; Hepatocytes/pathology ; Hepatocytes/cytology ; Proto-Oncogene Proteins c-myc/metabolism ; Proto-Oncogene Proteins c-myc/genetics ; TOR Serine-Threonine Kinases/metabolism ; Carcinoma, Hepatocellular/pathology ; Carcinoma, Hepatocellular/genetics ; Cyclin D1/metabolism ; Animals ; Mice ; Wnt Signaling Pathway ; Cell Proliferation ; Cell Differentiation ; Male ; Female ; Alleles ; MAP Kinase Signaling System ; Humans |
| Περίληψη: | Oncogenic mutations in phenotypically normal tissue are common across adult organs1,2. This suggests that multiple events need to converge to drive tumorigenesis and that many processes such as tissue differentiation may protect against carcinogenesis. WNT-β-catenin signalling maintains zonal differentiation during liver homeostasis3,4. However, the CTNNB1 oncogene-encoding β-catenin-is also frequently mutated in hepatocellular carcinoma, resulting in aberrant WNT signalling that promotes cell growth5,6. Here we investigated the antagonistic interplay between WNT-driven growth and differentiation in zonal hepatocyte populations during liver tumorigenesis. We found that β-catenin mutations co-operate with exogenous MYC expression to drive a proliferative translatome. Differentiation of hepatocytes to an extreme zone 3 fate suppressed this proliferative translatome. Furthermore, a GLUL and Lgr5-positive perivenous subpopulation of zone 3 hepatocytes were refractory to WNT-induced and MYC-induced tumorigenesis. However, when mutant CTNNB1 and MYC alleles were activated sporadically across the liver lobule, a subset of mutant hepatocytes became proliferative and tumorigenic. These early lesions were characterized by reduced WNT pathway activation and elevated MAPK signalling, which suppresses zone 3 differentiation. The proliferative lesions were also dependent on IGFBP2-mTOR-cyclin D1 pathway signalling, in which inhibition of either IGFBP2 or mTOR suppressed proliferation and tumorigenesis. Therefore, we propose that zonal identity dictates hepatocyte susceptibility to WNT-driven tumorigenesis and that escaping WNT-induced differentiation is essential for liver cancer. (© 2025. The Author(s).) |
| Competing Interests: | Competing interests: O.J.S. receives funding from Novartis, Cancer Research Technology (Cancer Research Horizons), Boehringer Ingelheim and AstraZeneca for other unrelated projects. H.Z. is a cofounder of Quotient Therapeutics and Jumble Therapeutics, advises for Newlimit, Alnylam Pharmaceuticals and receives funding from Chroma Medicines for other unrelated projects. H.C. is the head of PharmaResearch and Early Development at Roche; full disclosure is available at https://www.uu.nl/staff/JCClevers . M.B. has consulted for BIoNTech. All other authors declare no competing interests. |
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| Grant Information: | United Kingdom WT_ Wellcome Trust; R01 AA028791 United States AA NIAAA NIH HHS; R01 CA251928 United States CA NCI NIH HHS |
| Substance Nomenclature: | 0 (beta Catenin) 0 (Proto-Oncogene Proteins c-myc) EC 2.7.11.1 (TOR Serine-Threonine Kinases) 0 (CTNNB1 protein, mouse) 0 (Mutant Proteins) 0 (Myc protein, mouse) EC 2.7.1.1 (mTOR protein, mouse) 136601-57-5 (Cyclin D1) |
| Entry Date(s): | Date Created: 20251119 Date Completed: 20260114 Latest Revision: 20260420 |
| Update Code: | 20260420 |
| PubMed Central ID: | PMC12804091 |
| DOI: | 10.1038/s41586-025-09733-1 |
| PMID: | 41261129 |
| Βάση Δεδομένων: | MEDLINE |
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