Nature Communications published research on August 10, 2026, showing that β-catenin gene mutations fail to expand in healthy liver tissue but drive tumor growth as tissue integrity deteriorates. Researchers led by Fox Chase Cancer Center investigated how mutant hepatocytes respond to changing tissue environments in male mice.
In healthy liver tissue, hepatocytes carrying a single β-catenin mutation demonstrated negative cellular fitness. These mutant cells failed to undergo clonal expansion and suffered progressive attrition linked to oxidative stress and endoplasmic reticulum stress.
Cells carrying the same β-catenin mutation clonally expanded and promoted tumor formation when liver integrity degraded through chronic injury or aging. This adaptive shift was linked to the activation of the AKT-NRF2 signaling pathway.
Abhinav Illendula, Charles K. Hewett, and Yuki Hayata contributed equally to the study, which was submitted on January 30, 2026, and accepted on July 28, 2026. The authors obtained the Ctnnb1ex3fl/+ mouse strain from Makoto M. Taketo at Kyoto University and received electron microscopy support from Jeffrey Caplan and Shannon Modla at the Delaware Biotechnology Institute.
The research team received technical support from the Flow Cytometry Core and Laboratory Animal Facility at Fox Chase Cancer Center. Research funding was provided through National Institutes of Health grants CA191152, CA258224, and CA289703, alongside support from the W.W. Smith Charitable Fund awarded to Joan Font-Burgada.
Co-authors on the study held affiliations with Temple University's Lewis Katz School of Medicine, Universitat de Barcelona, Universidad Francisco de Vitoria, Children’s Hospital of Philadelphia, and Anhui Medical University.
