212: Zonal control of mutant β-catenin tumorigenesis

Raven A et al. - This study shows that hepatic zonation determines whether mutant β-catenin drives proliferation and liver cancer by forcing differentiation to a non-permissive zone 3 fate or, when reversed, enabling MAPK- and mTOR-dependent growth. Key terms: hepatic zonation, beta-catenin, MYC, mTOR, IGFBP2.

Study Highlights:
β-catenin exon 3 mutations cooperate with exogenous MYC to produce a proliferative translatome that supports tumour outgrowth. Differentiation to an extreme zone 3 GLUL+Lgr5+ hepatocyte fate suppresses the pro-growth translatome and is refractory to WNT/MYC-driven tumorigenesis. Early proliferative lesions that progress show reduced WNT activation, elevated MAPK signalling and engagement of an IGFBP2–mTOR–cyclin D1 axis, and inhibition of IGFBP2, mTOR or Yap/Taz impairs lesion formation and tumorigenesis. High-level WNT activation from Apc loss is less compatible with tumour formation, whereas MAPK activation (BrafV600E) antagonizes zone 3 differentiation to permit Lgr5+ hepatocyte transformation that can be suppressed by PORCN or BRAF inhibitors

Conclusion:
Hepatocyte zonal identity dictates susceptibility to WNT-driven HCC, and escape from WNT-induced zone 3 differentiation plus activation of MAPK/mTOR pro-growth pathways is required for tumour initiation

Music:
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First author:
Raven A

DOI:
10.1038/s41586-025-09733-1

Reference:
Raven A. et al. Hepatic zonation determines tumorigenic potential of mutant β-catenin. Nature. 2025. https://doi.org/10.1038/s41586-025-09733-1

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode link: https://basebybase.com/episodes/hepatic-zonation-wnt-tumorigenesis

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-28.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the main scientific narrative in the transcript: hepatic zonation, CTNNB1 mutations and MYC cooperation, zone 3 differentiation as tumor suppressor, the IGFBP2–mTOR–CCND1 axis, MAPK signaling and BRAF involvement, and pharmacological proof-of-concept (rapamycin, dabrafenib, LGK974).
- transcript topics: Hepatic zonation and WNT signaling; CTNNB1 exon 3 mutations and MYC cooperation; Zone 3 differentiation as tumor suppressor and zone 2 growth axis; IGFBP2–mTOR–CCND1 pro-growth axis; MAPK signaling and BRAF involvement in tumorigenesis; Ribosome profiling and translational control

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- CTNNB1 exon 3 mutations cooperate with MYC to drive a proliferative translatome
- 81% of CTNNB1-mutated tumors exhibit MYC copy-number gain
- Zone 3 GLUL+ Lgr5+ hepatocytes are refractory to WNT- and MYC-driven tumorigenesis
- Early proliferative lesions show reduced WNT activation and elevated MAPK signaling
- IGFBP2–mTOR–CCND1 axis supports lesion growth; IGFBP2/mTOR inhibition reduces tumorigenesis
- Rapamycin reduces lesion number and extends survival in mouse models; dabrafenib inhibits BRafV600E-driven tumor growth

QC result: Pass.