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How 'phenotype switching' can make melanoma become metastatic and resistant to drugs
Date:10/19/2013

rugs are not particularly effective in many patients, and many who do respond well to the drugs often eventually become resistant to them. This makes understanding advanced stages of melanoma and what internal processes could be at work all the more important for developing new treatments.

Weeraratna and her team focus on Wnt5A, a Wnt signaling molecule that has been found in increased levels in metastatic melanomas. In order for Wnt5A to promote the phenotype switch from early in the tumor's formation to the time it becomes metastatic, the tyrosine kinase receptor ROR2 is required. When ROR2 is not present, Wnt5A is unable to promote tumor metastasis. The only other member of the family that has been identified is ROR1, and this research was done to determine what role ROR1 might play in the progression of melanoma.

The researchers were able to determine that ROR1 inhibited the invasion of melanoma cells, and this receptor was targeted for degradation by Wnt5A and ROR2. When ROR1 was silenced, the researchers observed that there was an increased rate of invasion of melanoma cells both in vitro and in vivo. The researchers also found that hypoxia areas of low oxygen supply in the tumor is able to induce a switch from ROR1 to ROR2 and results in an increase in levels of Wnt5A, suggesting the switch from a non-invasive ROR1-positive phenotype to an invasive ROR2-positive phenotype occurs when the tumor is exposed to hypoxic conditions. The researchers also found that a protein HIF1α is required to increase the Wnt5A expressed. When HIF1α was removed, ROR2 was decreased, indicating that the upregulation of ROR2 via HIF1α requires Wnt5A.

To determine the clinical implications, the researchers hypothesized that melanoma cells driven by the mutant BRAF gene that were also high in Wnt5A might be less sensitive to treatment with vemurafenib, a drug approved by the FDA in 2011 for the treatment of BRAF-positive metastatic melanoma. By measuring
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Contact: Ben Leach
bleach@wistar.org
215-495-6800
The Wistar Institute
Source:Eurekalert

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