Adaptive oncogenesis of β-catenin emerges from declining liver tissue integrity

Abstract

Abstract Mutations are fundamental to oncogenesis, yet they cannot fully explain cancer progression, as oncogenic mutations frequently accumulate in healthy tissues without immediate malignancy. In the liver, β-catenin mutations are highly prevalent in hepatocellular carcinoma but are widely considered weak or cooperative drivers, raising the question of how their oncogenic potential is contextually regulated. Aging and chronic injury are major determinants of cancer risk. However, how declining tissue integrity reshapes the fitness of cells harboring oncogenic mutations remains poorly understood. Here we show that mutant β-catenin as a single genetic event confers negative fitness in the healthy liver of male mice, where mutant hepatocytes fail to clonally expand and undergo progressive attrition associated with oxidative and endoplasmic reticulum stress. In contrast, as liver tissue integrity declines during chronic injury or aging, cells carrying the same β-catenin mutation clonally expand and promote tumorigenesis, a process linked with activation of the AKT-NRF2 axis. These findings demonstrate that β-catenin mutations acting as single genetic lesions are maladaptive under normal liver homeostasis but become adaptive as tissue integrity deteriorates. This tissue-level shift reshapes the oncogenic fitness landscape, relaxing the constraints that normally prevent tumor initiation.