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Understanding the role of “phenotype switching” may help increase effectiveness of existing drugs and aid in the development of new ones for advanced melanoma

Melanoma is the rarest form of skin cancer, yet it is responsible for the most deaths related to the disease. While smaller tumors can usually be successfully treated with surgery, patients with advanced or metastatic melanoma – when the skin cancer has spread to other organs – have limited therapeutic options.

Now, researchers at The Wistar Institute are beginning understand the underlying mechanism behind what might drive metastasis in patients with melanoma. Their research involves phenotypes  (or outward, physical appearance) of tumor cells. They were able to identify a pathway that alters the phenotype, changing the way the tumor behaves and responds to therapy.

 “We were able to demonstrate for the first time that different receptors within a single signaling pathway – in this case, the Wnt signaling pathway – can guide the phenotypic plasticity of tumor cells, and increased signaling of Wnt5A in particular can result in an increase in highly invasive tumor cells that are less sensitive to existing treatments for metastatic melanoma,” said Ashani Weeraratna, Ph.D., assistant professor in the Tumor Microenvironment and Metastasis Program of Wistar’s NCI-designated Cancer Center, and senior corresponding author on the manuscript.

The researchers found that a molecule that signals the tumor cells to act a certain way called Wnt5A is found more frequently in metastatic melanomas. This molecule needs a protein called ROR2 to cause the melanoma’s cells phenotype to switch thereby causing the tumor to become metastatic. When ROR2 isn’t present, Wnt5A is unable to tell the cells to make that switch to become metastatic.

The ROR2 protein is related to the ROR1 protein, which is able to inhibit the melanoma cells from invading other organs. When the researchers disabled ROR1, the tumor cells became more metastatic. Low levels of oxygen in the tumor were responsible for causing ROR1 to become ROR2.

Wistar’s team found that tumors with high levels of Wnt5A might not respond as well when they received the drug vemurafenib, which was recently approved by the FDA in 2011 to treat certain types of metastatic melanoma. They were able to find that patients who had lower levels of Wnt5A had better responses to the drug.

“By using Wnt5A as a biomarker, we could determine which patients are likely to respond better to therapy with vemurafenib and help prolong that response,” Weeraratna said.  “There is also the potential to explore small molecule inhibitors of ROR2, since there is now a clear association between that and the ability of melanoma to become not only metastatic, but also therapy-resistant. This link between metastasis and therapy resistance is what we find the most exciting and intriguing, as therapies designed to target one process may have a significant impact on the other as well."