212: Zonal control of mutant β-catenin tumorigenesis

️ Episode 212: Zonal control of mutant β-catenin tumorigenesis 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 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. 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

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