The researchers deemed the findings ‘very important’ for patients with treatment-resistant forms of melanoma.
The new research was led by Craig J. Ceol, Ph.D., an assistant professor of molecular medicine at the University of Massachusetts Medical School (UMMS) in Boston. The findings were published in the Journal of Clinical Investigation.
The National Cancer Institute (NCI) estimate that 87,110 new cases of melanoma were diagnosed in 2017, and that 9,730 people have died from the disease.
“Although new therapies have shown effectiveness against melanoma, a majority of patients either do not respond to these therapies or develop resistance,” explains Ceol.
But the new findings bring much-needed hope. Ceol and his team discovered a gene that plays a key role in the advancement of melanoma, and the results may lead to a new drug target that could one day change therapeutic practices for this aggressive form of skin cancer.
The gene encodes a protein called GDF6, which is active during the development of the embryo. GDF6 is part of a class of proteins called “growth differentiation factors,” which are so named as they help cells to grow by dividing as well as help stem cells to differentiate into specific types of cell during the development of an embryo.
Why the GDF6 protein is key in metastasis
To isolate the genes that are crucial in the development of melanoma from those that are not, first study author Arvind Venkatesan — a Ph.D. candidate at UMMS — and colleagues used a zebrafish model, which they compared with human melanomas.
The researchers found 374 genes that were altered in both zebrafish melanomas and human ones. After sifting through the genes even further, using DNA, RNA, and protein expression analyses, GDF6 emerged as the potential genetic culprit for melanoma.
Further analyses shed more light on GDF6’s activity, revealing that the growth factor switched off two genes called MITF and SOX9. In a healthy body, these two genes enable cells to mature and die as per the normal cycle.
But when these two genes are switched off, cancer cells divide and spread freely. Ceol explains, “MITF is a master regulator of cell differentiation in melanocytes, which are the cells that form melanin pigment in the skin.”
“By turning off MITF,” he adds, “GDF6 keeps the cells from differentiating. Instead of differentiating, the cells keep dividing. Additionally, GDF6 also represses the expression of SOX9, which helps keep these melanoma cells alive.”
Hope for aggressive forms of melanoma
Importantly, the research also revealed that 80 percent of tumors from melanoma patients had high levels of GDF6, and the higher the levels of this protein were, the more aggressive the cancer was.
By contrast, in people with lower levels of GDF6, melanoma was less likely to metastasize, and the patients had better survival prospects.
“This is important because it means melanoma cells are dependent on GDF6 for survival,” says Venkatesan. “Without GDF6, melanoma cells do not survive.”
“What is so exciting about this discovery is that it opens up a completely new therapeutic target for investigation. None of the current therapies on the market target GDF6 or its pathway. For patients with very aggressive or treatment-resistant forms of this cancer, this is very important.”
Craig J. Ceol, Ph.D.
As Ceol continues, “[T]here is great therapeutic potential when you combine a drug targeting GDF6 with current therapeutics.” This is why he and his colleagues are currently working on a way to switch off the gene in a way that could be used therapeutically.
He adds, “Because GDF6 is a type of protein that acts outside the cell, it makes it much easier to target therapeutically. We’re already exploring how to use monoclonal antibodies to inhibit GDF6.”
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