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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. β-catenin is widely thought to be a major oncogene in HCC based on the frequency of mutations associated with aberrant Wnt signaling in HCC patients. Challenging this model, our data reveal that β-catenin nuclear accumulation is restricted to the late stage of the disease. Until then, β-catenin is primarily located at the plasma membrane in complex with multiple cadherin family members where it drives tumor cell survival by enhancing the signaling of growth factor receptors such as EGFR. Therefore, our study reveals the evolving nature of β-catenin in HCC to establish it as a compound tumor promoter during the progression of the disease. Aberrant Wnt/b-catenin signaling is thought to be a major driver of hepatocellular carcinoma. Here, the authors show that β-Catenin is predominantly integrated within the AJ complex during the early stages of this cancer and enhance EGFR signaling to promote tumour survival. [ABSTRACT FROM AUTHOR]