Review Article: β-Catenin-Driven Cancer Stemness in Colorectal Cancer: Molecular Targets and Therapeutic Opportunities

Colorectal cancer (CRC) remains a significant health challenge worldwide, and tumor recurrence, metastasis, and therapeutic resistance are mainly facilitated by cancer stem cells (CSC). Aberrant activation of the β-catenin driven Wnt signaling pathway, that fosters tumor initiation, self-renewal, and stemness-related gene expression, is central to the preservation of CSC properties. This review elucidates how β-catenin regulated transcriptional networks support CSC phenotypic nature such as self-renewal, differentiation potential, and survival advantages that make CRC aggressive. We discuss important β-catenin target genes and their roles in controlling stemness, proliferation, evasion of the immune system, chemoresistance and metabolic adaptation. We explore the challenges and knowledge gaps in therapeutic targeting of CRC including; tumor heterogeneity, tumor plasticity and absence of robust, predictive biomarkers. In our conclusion we discuss future directions toward better targeting of β-catenin-driven CSC programs that place importance on integrated, multi-modal approaches to target both the cellular and molecular heterogeneity of CRC with the goal of improving outcome and improving relapse rates.