How melanoma changes phenotype to resist treatment uncovered

Image of melanoma courtesy Wikimedia Commons
Melanoma is a deadly form of cancer that can become resistant to treatment and spread rapidly. Researchers have now uncovered how melanoma changes its genetic coding to escape destruction and spread throughout the body.

What the finding means to patients being treated for the disease is more targeted therapy.

Phenotype switching changes melanoma’s appearance

According to the research published in the journal Cancer Discovery, a process known as phenotype switching” may be involved in how melanoma tumors change their appearance.  

“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 in a press release.

The researchers focused on the Wnt5A signaling pathway after noticing the molecule was high in melanoma skin cancer cells.

Melanoma switches is phenotype to become metastatic with the help of the tyrosine kinase receptor ROR2. Without ROR2 melanoma can’t spread.
ROR1 is the only molecule that has been identified that promotes melanoma metastasis. The researchers conducted the current study to find out the role of ROR1.

What the researchers found was that ROR1 slows invasion of melanoma and ROR2 and Wnt work together to degrade ROR1.

The scientists observed melanoma becoming more invasive when the ROR1 molecule was silenced.

They also found that low oxygen supply in melanoma tumors causes a switch from ROR1 to ROR2 that leads to higher levels of Wnt5A that also depends on the presence of the protein HIF1α. Removing HIF1α decreased ROR2.

Finally, they looked at patients being given the drug vemurafenib, used to treat BRAF-positive metastatic melanoma.

They found 7 of 9 patient’s melanoma who responded poorly to vemurafenib expressed Wnt5A.

Just two of the remaining 15 patients who had a 38 percent or better response to the chemotherapy had any expression of Wnt5A.

The finding links melanoma that resists treatment to Wnt5A expression.

"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."

The best treatment for melanoma is when it is caught early. Anyone can be affected by melanoma that kills 85 percent of people when it is diagnosed late.

The ABCDE of  identifying melanoma

Symptoms of melanoma include moles that are irregular or Asymmetric, the Borders are irregular, moles that are two different Colors; the Diameter is larger than a pencil eraser and the mole changes or Evolves in appearance.

Understanding more about melanoma, the most deadly form of skin cancer, can help with new drug development. The new study uncovers how melanoma changes its phenotype to resist drug therapy and spread. Understanding melanoma phenotypes in individual patients could help survival.