️ 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.

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