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:Enjoy the music based on this article at the end of the episode. 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/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. 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 m... Chapters (00:00:00) - Base by Bass(00:02:20) - Hepatic zonation 6, The liver paradox(00:03:35) - How does wnt signaling cause cancer?(00:06:28) - WNT mutations in the liver