Research linking autophagy with the Wnt signaling pathway, a key regulator of melanoma progression and metastasis, may guide effective use of autophagy inhibitors.

The findings appear online in Cancer Research.

Autophagy allows cancer cells to survive under stressful conditions in the tumor microenvironment. Because it also affects the response to melanoma targeted therapy, several studies are investigating the potential of inhibiting autophagy as a strategy to improve sensitivity to targeted therapy, with some autophagy inhibitors currently moving into clinical trials.

“We have already shown that Wnt5A, a component of the Wnt pathway, plays critical roles in melanoma progression,” says Ashani Weeraratna, Ph.D., Ira Brind Associate Professor and co-program leader of the Immunology, Microenvironment and Metastasis Program at the Wistar Institute in Philadelphia and corresponding author of the paper, in a news release. “Our new study indicates a link between the Wnt pathway and autophagy, whereby Wnt is a key player in the response to autophagy inhibitors and likely affects the efficacy of this class of drugs.”

Weeraratna and colleagues assessed the interplay between Wnt5A, a key molecule in the Wnt pathway, and autophagy by combining expression studies in human melanoma biopsies with functional analyses in cell lines and mouse models. In particular, they found a direct correlation between expression levels of Wnt5A, which also correlate with melanoma progression, and activation of autophagy. They then observed a reciprocal regulation of autophagy and Wnt signaling. This prompted them to test in vitro and in vivo how the response of melanoma to an autophagy inhibitor is affected by Wnt signaling activation.

They observed that cells with high levels of Wnt5A and autophagy activation are less sensitive and require higher concentrations of the inhibitor. They also found that the pharmacological modulation of another molecule of the Wnt pathway, β-catenin, significantly improves the response of aggressive melanoma cells to autophagy inhibition, lowering the dose required to eradicate these cells.

“By dissecting the crosstalk between the autophagy pathway and the Wnt pathway, we discovered that signaling changes that occur within the tumor may affect the response to autophagy inhibitors,” says Abibatou Ndoye, a graduate student in the Weeraratna lab and first author of the study. “Our observations will be helpful to determine which patients will be more responsive to this therapeutic strategy and how we can target the pathways that affect the response, in order to overcome resistance.”