A1 Refereed original research article in a scientific journal
Hepatic zonation determines tumorigenic potential of mutant β-catenin
Authors: Raven, Alexander; Gilroy, Kathryn; Jin, Hu; Waldron, Joseph A.; Leslie, Holly; Munro, June; Hall, Holly; Ridgway, Rachel A.; Ford, Catriona A.; Gulhan, Doga C.; Vlahov, Nikola; Mills, Megan L.; Hartley, Andrew; Anderson, Eve; Bryson, Sheila; Sphyris, Nathalie; Müller, Miryam; May, Stephanie; Cadden, Barbara; Nixon, Colin; Waddell, Scott H.; Guest, Rachel; Boulter, Luke; Barker, Nick; Clevers, Hans; Zhu, Hao; Ivaska, Johanna; Strathdee, Douglas; Miller, Crispin J.; Jamieson, Nigel B.; Bushell, Martin; Park, Peter J.; Bird, Thomas G.; Sansom, Owen J.
Publisher: Springer Nature
Publication year: 2025
Journal: Nature
ISSN: 0028-0836
eISSN: 1476-4687
DOI: https://doi.org/10.1038/s41586-025-09733-1
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Partially Open Access publication channel
Web address : https://doi.org/10.1038/s41586-025-09733-1
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/505542677
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.
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Funding information in the publication:
O.J.S. and his laboratory members and S.M. were supported by Cancer Research UK (A29055, A28223, A21139, DRCQQR-May21\100002 and CTRQQR-2021\100006). A.R. and K.G. were supported by the SPECIFICANCER Cancer Research UK Grand Challenge Award (A29055 to O.J.S.). C.A.F. was supported by the Rosetta Cancer Research UK Grand Challenge Award (A25045 to O.J.S.). R.A.R. and N.S. were supported by Cancer Research UK core funding to the Scotland Institute (A17196 and A31287) and the Colorectal Cancer and WNT signalling group (A21139 and DRCQQR-May21\100002 to O.J.S.). N.V. was supported by the Wellcome Trust (201487 to O.J.S.). M.L.M. was supported by a CRUK Accelerator Award (A28223 to O.J.S.). H.J., D.C.G. and P.J.P. were supported by the SPECIFICANCER Cancer Research UK Grand Challenge and an award from the Mark Foundation for Cancer Research to the SPECIFICANCER team. J.I. was supported by a Sigrid Juselius Foundation Senior Fellowship. M.M. and T.G.B. were funded by the Wellcome Trust and the CRUK Scotland Centre (WT107492Z and CTRQQR-2021\100006) and CRUK Accelerator (A26813). The human HCC results shown here are in whole or part based on data generated by the TCGA Research Network (https://www.cancer.gov/tcga). H.Z. is supported by NIH R01 grants (CA251928 and AA028791), the Simmons Comprehensive Cancer Center, and the Emerging Leader Award from the Mark Foundation for Cancer Research (no. 21-003-ELA). S.H.W. is funded by a Chief Scientist Office Early Postdoctoral Fellowship (EPD/22/12) and a Research Incentive Grant (RIG012508) from The Carnegie Trust for the Universities of Scotland. L.B. is funded by Cancer Research UK (C52499/A27948, CTRQQR-2021\100006 and PRCBTP-May24/100001) and UKRI MRC (MR/Z506199/1).
