This image shows a zebrafish with a melanoma that has spread, or metastasized, throughout the body. The tumors are clearly visible because they produce a marker protein that gives off a green glow, and the fish, unlike ordinary zebrafish, is see-through.
Memorial Sloan Kettering physician and researcher Richard M. White generated this transparent and stripeless strain of zebrafish to allow researchers to visualize the growth and spread of tumors in a whole animal. He is using the fish, which he named Casper after the cartoon ghost, to study metastasis – the process whereby cancer cells escape from a primary tumor, enter the bloodstream, and take root in a new location to propagate additional tumor growth.
Although metastasis is responsible for the majority of cancer deaths, we know very little about how it happens or how to prevent it. “As an oncologist I found it incredible that survival rates from metastatic cancer are essentially unchanged since the 1960s,” says Dr. White. Frustrated by the slow rate of progress, he adopted an innovative approach to the problem of metastasis using zebrafish and evolutionary biology methods.
Zebrafish are emerging as a powerful tool in cancer research. The fish succumb to many of the same cancers as humans, including melanoma and blood cancers. They are also small, cheap, and highly amenable to genetic manipulation, making them an ideal model to systematically screen thousands of genes.
Casper provides the Memorial Sloan Kettering team with a rapid visual readout of metastasis and allows them to probe the complex interplay of genes at work in the tumor cells and in the noncancerous tissues they invade.
An Evolutionary Idea
Metastasis is a highly unpredictable process, and the genes involved are likely to differ from patient to patient. Dr. White’s ultimate goal is to identify the root causes of metastasis common to all patients.
“There may be a hundred different ways for a tumor to metastasize,” he explains. “Rather than looking at the multitude of individual genes responsible, we are asking, What are the underlying processes that drive the tumor cells to do this?”
Using Casper and other zebrafish models, his team is investigating how tumors evolve the capacity to metastasize. One theory is that stressful conditions within the tumor, such as low oxygen, trigger tumor cells to diversify their genes, allowing them to evolve new traits and exit the tumor.
Dr. White predicts that interfering with tumor evolution, for example by alleviating tumor cell stress, could provide radical new approaches to treat cancer that would not eliminate the tumor but would prevent metastasis.
In September 2013, he was awarded a $1.5 million National Institutes of Health Director’s New Innovator Award to pursue his evolutionary approach to metastasis. These prestigious awards are specifically designed to support innovative and high-risk research.
Read a story in The Scientist co-authored by Dr. White to learn more about how zebrafish are advancing our understanding of cancer development.