Study Shows How Melanoma can Become Drug Resistant

A process involving the phenotypes of tumor cells could change the appearance of melanoma tumors, say researchers. Identifying the phenotype patients exhibit may help determine which patients are more likely to benefit from existing medications while also providing an opportunity to create new targeted therapies.

Senior correspond author Ashani Weeraratna, Ph.D., Assistant Professor in the Tumor Microenvironment and Metastasis Program of Wistar’s NCI-designated Cancer Center, 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 HIF1a is required to increase the Wnt5A expressed. When HIF1a was removed, ROR2 was decreased, indicating that the up regulation of ROR2 via HIF1a requires Wnt5A.

The findings have been published online in the journal Cancer Discovery.

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