Hepatic zonation determines tumorigenic potential of mutant β-catenin

Alexander Raven; Kathryn Gilroy; Hu Jin; Joseph A. Waldron; Holly Leslie; June Munro; Holly Hall; Rachel A. Ridgway; Catriona A. Ford; Doga C. Gulhan; Nikola Vlahov; Megan L. Mills; Andrew Hartley; Eve Anderson; Sheila Bryson; Nathalie Sphyris; Miryam Müller; Stephanie May; Barbara Cadden; Colin Nixon; Scott H. Waddell; Rachel Guest; Luke Boulter; Nick Barker; Hans Clevers; Hao Zhu; Johanna Ivaska; Douglas Strathdee; Crispin J. Miller; Nigel B. Jamieson; Martin Bushell; Peter J. Park; Thomas G. Bird; Owen J. Sansom

doi:10.1038/s41586-025-09733-1

Hepatic zonation determines tumorigenic potential of mutant β-catenin

Alexander Raven
, Kathryn Gilroy
, Hu Jin
, Joseph A. Waldron
, Holly Leslie
, June Munro
, Holly Hall
, Rachel A. Ridgway
, Catriona A. Ford
, Doga C. Gulhan
, Nikola Vlahov
, Megan L. Mills
, Andrew Hartley
, Eve Anderson
, Sheila Bryson
, Nathalie Sphyris
, Miryam Müller
, Stephanie May
, Barbara Cadden
, Colin Nixon

Scott H. Waddell, Rachel Guest, Luke Boulter, Nick Barker, Hans Clevers, Hao Zhu, Johanna Ivaska, Douglas Strathdee, Crispin J. Miller, Nigel B. Jamieson, Martin Bushell, Peter J. Park, Thomas G. Bird, Owen J. Sansom^*

^*Corresponding author for this work

Turku Bioscience Centre

Research output: Contribution to journal › Article › Scientific › peer-review

2 Citations (Scopus)

Abstract

Oncogenic mutations in phenotypically normal tissue are common across adult organs^1,2. 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 homeostasis^3,4. However, the CTNNB1 oncogene—encoding β-catenin—is also frequently mutated in hepatocellular carcinoma, resulting in aberrant WNT signalling that promotes cell growth^5,6. 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.

Original language	English
Pages (from-to)	739-748
Number of pages	10
Journal	Nature
Volume	649
Issue number	8097
DOIs	https://doi.org/10.1038/s41586-025-09733-1
Publication status	Published - 15 Jan 2026
MoE publication type	A1 Journal article-refereed

Funding

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. We thank the Core Services and Advanced Technologies at the Cancer Research UK Scotland Institute (funded by Cancer Research UK core funding A17196 and A31287)—particularly the Biological Services Unit, the Transgenic Technology service, Bioinformatics service, the Histology Service and the Molecular Technologies service—for technical support; C. Winchester at the Cancer Research UK Scotland Institute for advising on manuscript preparation; and members of the Sansom laboratory and SPECIFICANCER Cancer Research UK Grand Challenge consortium for discussions of the data and manuscript. 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). The mouse and viral diagrams were obtained from Servier Medical Art (https://smart.servier.com/smart_image/mouse-3/ and https://smart.servier.com/smart_image/adenovirus-molecule/) and are licensed under a CC BY 4.0 licence. Other diagrams were generated using BioRender (http://biorender.com). We thank the Core Services and Advanced Technologies at the Cancer Research UK Scotland Institute (funded by Cancer Research UK core funding A17196 and A31287)—particularly the Biological Services Unit, the Transgenic Technology service, Bioinformatics service, the Histology Service and the Molecular Technologies service—for technical support; C. Winchester at the Cancer Research UK Scotland Institute for advising on manuscript preparation; and members of the Sansom laboratory and SPECIFICANCER Cancer Research UK Grand Challenge consortium for discussions of the data and manuscript. 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). The mouse and viral diagrams were obtained from Servier Medical Art ( https://smart.servier.com/smart_image/mouse-3/ and https://smart.servier.com/smart_image/adenovirus-molecule/ ) and are licensed under a CC BY 4.0 licence. Other diagrams were generated using BioRender ( http://biorender.com ).

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Cite this

Raven, A., Gilroy, K., Jin, H., Waldron, J. A., Leslie, H., Munro, J., Hall, H., Ridgway, R. A., Ford, C. A., Gulhan, D. C., Vlahov, N., Mills, M. L., Hartley, A., Anderson, E., Bryson, S., Sphyris, N., Müller, M., May, S., Cadden, B., ... Sansom, O. J. (2026). Hepatic zonation determines tumorigenic potential of mutant β-catenin. Nature, 649(8097), 739-748. https://doi.org/10.1038/s41586-025-09733-1

@article{25f8619083a84f5f97db97319cff689c,

title = "Hepatic zonation determines tumorigenic potential of mutant β-catenin",

abstract = "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.",

keywords = "Cancer genetics, Mutation, Liver cancer, Cancer models",

author = "Alexander Raven and Kathryn Gilroy and Hu Jin and Waldron, \{Joseph A.\} and Holly Leslie and June Munro and Holly Hall and Ridgway, \{Rachel A.\} and Ford, \{Catriona A.\} and Gulhan, \{Doga C.\} and Nikola Vlahov and Mills, \{Megan L.\} and Andrew Hartley and Eve Anderson and Sheila Bryson and Nathalie Sphyris and Miryam M{\"u}ller and Stephanie May and Barbara Cadden and Colin Nixon and Waddell, \{Scott H.\} and Rachel Guest and Luke Boulter and Nick Barker and Hans Clevers and Hao Zhu and Johanna Ivaska and Douglas Strathdee and Miller, \{Crispin J.\} and Jamieson, \{Nigel B.\} and Martin Bushell and Park, \{Peter J.\} and Bird, \{Thomas G.\} and Sansom, \{Owen J.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2026",

month = jan,

day = "15",

doi = "10.1038/s41586-025-09733-1",

language = "English",

volume = "649",

pages = "739--748",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "8097",

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Raven, A, Gilroy, K, Jin, H, Waldron, JA, Leslie, H, Munro, J, Hall, H, Ridgway, RA, Ford, CA, Gulhan, DC, Vlahov, N, Mills, ML, Hartley, A, Anderson, E, Bryson, S, Sphyris, N, Müller, M, May, S, Cadden, B, Nixon, C, Waddell, SH, Guest, R, Boulter, L, Barker, N, Clevers, H, Zhu, H, Ivaska, J, Strathdee, D, Miller, CJ, Jamieson, NB, Bushell, M, Park, PJ, Bird, TG & Sansom, OJ 2026, 'Hepatic zonation determines tumorigenic potential of mutant β-catenin', Nature, vol. 649, no. 8097, pp. 739-748. https://doi.org/10.1038/s41586-025-09733-1

TY - JOUR

T1 - Hepatic zonation determines tumorigenic potential of mutant β-catenin

AU - Raven, Alexander

AU - Gilroy, Kathryn

AU - Jin, Hu

AU - Waldron, Joseph A.

AU - Leslie, Holly

AU - Munro, June

AU - Hall, Holly

AU - Ridgway, Rachel A.

AU - Ford, Catriona A.

AU - Gulhan, Doga C.

AU - Vlahov, Nikola

AU - Mills, Megan L.

AU - Hartley, Andrew

AU - Anderson, Eve

AU - Bryson, Sheila

AU - Sphyris, Nathalie

AU - Müller, Miryam

AU - May, Stephanie

AU - Cadden, Barbara

AU - Nixon, Colin

AU - Waddell, Scott H.

AU - Guest, Rachel

AU - Boulter, Luke

AU - Barker, Nick

AU - Clevers, Hans

AU - Zhu, Hao

AU - Ivaska, Johanna

AU - Strathdee, Douglas

AU - Miller, Crispin J.

AU - Jamieson, Nigel B.

AU - Bushell, Martin

AU - Park, Peter J.

AU - Bird, Thomas G.

AU - Sansom, Owen J.

PY - 2026/1/15

Y1 - 2026/1/15

N2 - 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.

AB - 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.

KW - Cancer genetics

KW - Mutation

KW - Liver cancer

KW - Cancer models

UR - https://www.scopus.com/pages/publications/105022459104

U2 - 10.1038/s41586-025-09733-1

DO - 10.1038/s41586-025-09733-1

M3 - Article

C2 - 41261129

AN - SCOPUS:105022459104

SN - 0028-0836

VL - 649

SP - 739

EP - 748

JO - Nature

JF - Nature

IS - 8097

ER -

Hepatic zonation determines tumorigenic potential of mutant β-catenin

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