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Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of β-catenin, which also promotes invasion. In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Melanoma cells with high Wnt5A and low β-catenin displayed increased basal autophagy. Genetic blockade of autophagy revealed an unexpected feedback loop whereby knocking down the autophagy factor ATG5 in Wnt5A high cells decreased Wnt5A and increased β-catenin. To define the physiologic relevance of this loop, melanoma cells with different Wnt status were treated in vitro and in vivo with the potent lysosomotropic compound Lys05. Wnt5A high cells were less sensitive to Lys05 and could be reverted by inducing β-catenin activity. Our results suggest the efficacy of autophagy inhibitors might be improved by taking the Wnt signature of melanoma cells into account. Cancer Res; 77(21); 5873-85. ©2017 AACR ., (©2017 American Association for Cancer Research.)

The outgrowth of metastatic and therapy-resistant subpopulations in cancer remains a critical barrier for the successful treatment of this disease. In melanoma, invasion and proliferation are uncoupled, such that highly proliferative melanoma cells are less likely to be invasive, and vice versa. The transition between each state is likely a dynamic rather than a static, permanent change. This is referred to as "phenotype switching". Wnt signaling pathways drive phenotypic changes and promote therapy resistance in melanoma, as well as play roles in the modulation of the immune microenvironment. Three Wnt signaling pathways play a role in melanoma progression, canonical (β-catenin dependent), polar cell polarity (PCP), and the Wnt/Ca²⁺ pathway. Here we summarize phenotype plasticity and its role in therapy resistance and immune evasion. Targeting the Wnt signaling pathways may be an effective way to overcome tumor plasticity in melanoma., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Wnt signaling in melanoma is complex, requiring the coordinate expression of multiple players. Depending on the context of receptors and co-receptors that are present, Wnt proteins may signal through either canonical or noncanonical pathways. The role of β-catenin in melanoma metastasis remains unclear; however, a new study points to the roles of Wnt5A and ARF6 in driving β-catenin expression and melanoma metastasis. Here, we discuss this finding and how it may help us define different subpopulations of melanoma cells that could have different outcomes, as well as different responses to therapy.