Mouse model aids discovery of novel melanoma metastasis gene

Mouse-human comparison proves an asset for cancer genomics

BOSTON--Researchers from Dana-Farber Cancer Institute have identified a novel gene that facilitates the spread of malignant melanoma, a life-threatening skin cancer, using a technique they say can speed the discovery of hard-to-find cancer genes.

In the June 30 issue of Cell, scientists led by Lynda Chin, MD, report that the gene, NEDD9, is abnormally abundant in more than a third of melanomas that have metastasized, but not in primary melanomas that have not spread.

The protein made by the NEDD9 gene allows the cancer cells to migrate beyond the initial skin tumor, to invade surrounding tissues and ultimately to metastasize to distant organs. While the protein itself does not lend itself to targeting by cancer drugs, say the researchers, insights gained in this study suggest that disrupting genes and proteins associated with NEDD9 may be fruitful in halting spread of melanoma.

"This is clinically important," said Chin, "because primary skin melanoma doesn't kill patients metastases are the major problem. So understanding the events that drive metastasis may lead to identifying the most relevant targets for therapy, and potentially, for preventing metastasis."

More than 62,000 cases of melanoma will be diagnosed in the United States this year, according to American Cancer Society estimates, and about 7,900 people will die of the cancer.

Chin and her group at Dana-Farber use genome-scanning methods such as array-CGH (comparative genomic hybridization) to uncover structural abnormalities of the chromosomes of cancer cells. In one common form of abnormality, bits of DNA have been overcopied (amplified) or, conversely, have been lost (deleted), and these "copy number alterations" are key events in the development and progression of cancers.

If the alterations are confined to a very small part of the chromosome, it is relatively easy to identify the likely culprits involved in the cancer. But in some cancers, including metastatic melanoma, scientists have discovered large regions of chromosomal DNA that have been amplified or deleted. In such cases, it would be a daunting task to pinpoint the actual gene culprit among a large number of "bystander" gene abnormalities that may not be relevant to the cancer.

For example, scientists had previously shown that the entire short arm of Chromosome 6, referred to as 6p, is amplified in more than 35 percent of cells from melanoma tumors that had metastasized. But the 6p region is only rarely amplified in primary, non-spreading melanomas. There are hundreds of genes on 6p, making the task of narrowing down to a few candidate culprits nearly impossible. Chin had previously created transgenic mice in which melanoma could be induced by turning cancer genes on or off. When tumors from these mice were transplanted into normal mice lacking an immune system, the cancers grew and a few of them became metastatic. Genome scans of the metastatic tumors -- known as "escapers" -- revealed an amplified region on Chromosome 13 that was not present in the primary (non-metastatic) tumor cells. That region, presumably, reflected a genetic change that promoted metastasis.

Although it is located on Chromosome 13 in the mouse, the amplified region was similar to the amplified region on Chromosome 6 in human melanoma cells, but, fortunately, it contained only eight genes. Therefore it was possible to pinpoint the NEDD9 gene in the mouse tumors and verify that the same gene in humans, when overactive, drives metastasis of melanoma tumors.

"This is a demonstration of the principle, that the mouse has similar genomic changes that are important for cancer, and we can use the mouse model as a 'filter' to help us identify which gene is responsible for the cancer development and metastasis," said Chin, who is also an associate professor of dermatology at Harvard Medical School.

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Lead author on the paper is Minjung Kim, PhD, in Chin's laboratory; other authors are from Brigham and Women's and Massachusetts General hospitals, Memorial-Sloan-Kettering Cancer Center, The Broad Institute of the Massachusetts Institute of Technology and Harvard; and the universities of Porto, Portugal, and Vienna, Austria.

The research was supported by the National Institutes of Health.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.


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