Even though fruit flies and humans are separated by 800 million years of evolution, a human gene can suppress the growth of tumors when transplanted into a type of fruit fly called Drosophila, according to School of Medicine researchers, who have identified the gene in humans and mice.

By creating fruit flies that exhibit mutations akin to those found in some human cancer patients, geneticist Tian Xu and his colleagues have identified a new type of tumor suppressor gene that may yield insights into some little-understood human cancers. Their research is reported in the February issue of the journal Nature Genetics.

"We have 'rescued' fruit flies from tumors by inserting a cancer-suppressing human gene into the insects' genetic blueprint," says Xu, an associate professor in the department of genetics and the Boyer Center for Molecular Medicine, a member of the Yale Cancer Center and an assistant investigator with the Howard Hughes Medical Institute (HHMI) at Yale. The researchers believe this achievement represents the first direct link between human tumor suppressor genes and those found in fruit flies.

Tumor suppressor genes produce proteins that normally stop cell proliferation. When such genes malfunction, they produce defective proteins that permit cells to proliferate endlessly, producing tumors. Specifically, the researchers showed that inserting the human "large tumor suppressor" (LATS1) gene into Drosophila that lacked the fly version of the gene (lats) prevented tumor formation. Flies with the human LATS1 gene did not show the widespread tumors and early mortality caused by the non-functioning lats gene, suggesting that the two genes have the same function.

In addition, Xu and his colleagues uncovered evidence that lats is a previously unknown kind of tumor suppressor that blocks a specific stage of cell proliferation. "We believe this finding represents a major advance in understanding cell-cycle regulation, and thus cancer biology itself. These LATS molecules are a new type of 'negative' regulators for the enzymes that drive the cell cycle," Xu says. The finding also hints that further study of the molecular-signaling machinery involving LATS1 could lead to new cancer therapies.

In another set of closely related experiments described in a second paper in the same issue of Nature Genetics, Xu's team disrupted the LATS1 gene in mice. The scientists found that these mice developed ovarian tumors, soft-tissue sarcomas and pituitary disorders.

"This finding is important because it is the first example showing that an invertebrate tumor suppressor is also a tumor suppressor in mammals," Xu says. "This also suggests that some human cancers may be caused by a mutation of the LATS1 gene, although the correlation between mice and humans is not that good in terms of the types of tumors caused by a particular mutation."

In a commentary on the two Yale papers, cancer researcher Christopher Kemp of the Fred Hutchinson Cancer Research Center in Seattle noted that, even though many tumor suppressor genes have been identified in flies, they "had not gained broad acceptance or notice in the mammalian cancer genetics community." But the two papers by Xu's team "take the study of fly cancer to a new level," Kemp wrote. "These show, apparently for the first time, that a gene functions as a tumor suppressor in both invertebrates and vertebrates. In two fell swoops, the authors have thrust a previously obscure fly mutation to the center of the cell cycle and mammalian cancer."

A key to the experiments was Xu's technique for producing "genetic mosaic" fruit flies. In such mosaics, researchers can manipulate selected cells to give them two copies of a defective tumor suppressor gene. "These mosaic flies are like cancer patients in that very few cells possess mutated tumor suppressors. But those cells, left unchecked, can develop into tumors," explains Xu. "Most of the cells in both the flies' and the human patients' bodies carry normal copies of these genes.

"We have shown that the process of tumor formation in flies is directly relevant to what happens in mammals, including humans, thus Drosophila is an excellent model to study cancer biology," Xu says. "With the power of the genetic manipulations that are available to this organism, fruit flies are destined to provide many new insights about cancers in humans."