Wnt/β-catenin signaling in melanoma: Preclinical rationale and novel therapeutic insights

• WNT signaling fundamentally regulates the embryonic development in many aspects, as well as tissue homeostasis in adult stage.
• WNT signaling is involved in melanoma progression through regulating cell proliferation and invasion, modulating the immune microenvironment, and promoting resistance in targeted therapies.
• Targeting the WNT signaling pathways may be potentially an effective strategy to overcome tumour plasticity in melanoma.

WNT signaling regulates embryonic development and tissue homeostasis in the adult stage. Evolutionarily, activation of the WNT pathway is triggered by a large family of cytokines and activates a broad spectrum of downstream targets through two independent branches mediated by β-catenin (defined as canonical pathway) or PLC and small GTPase (defined as non-canonical pathway), respectively. Recent studies revealed the crucial role of WNT in the maintenance of cell metabolism and stemness as well as its deregulation in tumourigenesis and malignant transformation through oncogenic reprogramming, which contributes to cancer cell proliferation and differentiation, survival, stress response and resistance. In addition, multiple functional mutations discovered in human tumours have been reported to cause malignancy, indicating this pathway as a novel therapeutic target in oncology. Notably, emerging data highlights its involvement in the crosstalk between immune and cancer cells. However, contradictory effects have been also observed in different pre-clinical models when strategic(???) inhibitors are tested. In this review, we address the multifaceted regulatory mechanisms of WNT signaling in cancer, with a particular focus on current melanoma therapy, which has witnessed dramatic improvement in the last five years.