Lowly Fruit Fly Reveals Genetic Factors in Cancer and Metastasis
For more than a century, Drosophila melanogaster, a species of common fruit fly, has been an indispensable model organism for genetics research. These flies thrive in the laboratory with minimal care and expense, reproduce rapidly, and possess an easily manipulated genome. The entire Drosophila genetic code has been sequenced, and Drosophila and humans share many genes that are known to cause disease.
Flies with a mutation in the RET oncogene, which leads to medullary thyroid cancer in humans, develop rough, non-functional eyes (middle). Treatment with the drug ZD6474, which targets RET, restored the eye cells to normal (right). A normal eye from a fly without the RET mutation is shown on the left for comparison. (Image courtesy of Dr. Marcos Vidal and Dr. Ross Cagan)
However, the use of Drosophila in cancer genetics has been fairly limited until recently. “Historically, people thought that Drosophila never grow tumors,” explained Dr. Tian Xu, professor of genetics at Yale University and an investigator with the Howard Hughes Medical Institute, whose laboratory has been testing uses for Drosophila in cancer research since 1993.
Early experiments where germline mutations (mutations in eggs or sperm) in genes suspected of playing a role in cancer development were introduced into fly lines failed: These flies carried the mutations in every cell in their body, and their offspring were not viable—they died in the embryonic stage.
Mimicking Human Tumor Formation
To create a model system that more closely mimicked human tumor formation, Dr. Xu's laboratory developed a genetic mosaic model that allowed them to mutate genes in individual somatic cells at different stages of a fly's development. These flies successfully matured and developed tumors in the target organs.
Dr. Xu and his colleagues have since used their mosaic model to identify and study many tumor suppressor genes in Drosophila that were later recognized as having orthologs (genes derived from a common evolutionary ancestor) or conserved properties in humans, such as PTEN's role in regulating cell growth. They also used Drosophila to elucidate the cell signaling pathway involved in tuberous sclerosis complex (TSC), a genetic disorder in which tumors form in many organs. They found that blocking downstream components of the pathway can suppress TSC-associated tumor formation. Now, the drug rapamycin, an inhibitor of the pathway, is being tested in clinical trials for TSC and brain tumors.
“When we first proposed studying tumor suppressors in flies, I didn't really imagine that our research could directly contribute to treatment in patients, so this was a really satisfying experience,” said Dr. Xu.
In recent years, his laboratory has focused on developing a Drosophila model of metastasis, which can be used to interrogate the contribution of individual genes to a cell's metastatic potential.
A Model of Tumor and Environment
Metastasis is also of great interest to Dr. Ross Cagan, professor of developmental and regenerative biology at the Mount Sinai School of Medicine. Originally trained in using Drosophila to test the cell signaling pathways that drive eye development, Dr. Cagan has developed several model systems that use Drosophila to directly screen potential anti-cancer and anti-metastasis drugs.
“Drosophila is the simplest model system that has classic epithelial tissues, with tumors that would actually react to drugs in the way they would in humans,” said Dr. Cagan. In addition, he explained, the sophisticated genetic tools available to Drosophila investigators allow them to insert four or more genes together into a fly chromosome. “We're looking at human sequencing data and asking what genes work together to form tumors. Then we can actually build those constructs in the fly,” he explained.
An early success for the Cagan laboratory came from their Drosophila model of MEN2 syndrome, an inherited condition that can result in the development of endocrine cancers, particularly medullary thyroid cancer (MTC). Dr. Cagan's laboratory created flies that expressed the aberrant protein responsible for MEN2-associated MTC in their eyes, which developed rough and non-functional cells. The investigators then fed the flies drugs that could potentially suppress the aberrant protein, until they found one that restored the eyes to normal. That compound, called ZD6474 (Zactima), is now being tested in a phase II clinical trial for MTC.
Dr. Cagan's laboratory has also developed a Drosophila model to test drugs targeting metastatic cancer cells. In their new model, the investigators have created a multi-gene system that causes cells in the fly wing to shed into the circulatory system as the fly develops (in the same way that metastatic cells leave a tumor), leaving the wing crumpled. The investigators then feed the flies potential anti-metastasis drugs and observe which compounds uncrumple the fly wing—in effect, reversing metastasis.
Since cancer progression and metastasis involve extensive interactions between cells and their environment, he explained, using flies instead of cell lines to screen drugs allows you to look at how a drug might affect these interactions in whole tissues. “If you want to look for effective anti-metastatic drugs,” he concluded, “you have to do it in a complete tumor, in a living system.”