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A partnership that aids cancer’s migration

Yale Medicine Magazine, 2004 - Spring


When Ras teams up with cell polarity genes, mutations are found to produce metastatic tumors.

In the world of cancer-causing genes, Ras is a celebrity. Mutated versions of this gene appear in more than half of all human cancers, including metastatic cancers, in which cells from a primary tumor disperse to other organs or systems of the body and there give rise to new tumors. Clearly, Ras is a culprit in many terminal cases. But since a large number of Ras-based tumors are benign and never spread beyond their original site, it was thought that the oncogenic Ras triggers only tumorigenesis. Now, research demonstrates that Ras also contributes to metastasis and it collaborates with a partner to do so. Tian Xu, Ph.D. ’90, professor and vice chair of the Department of Genetics and an associate investigator for the Howard Hughes Medical Institute (HHMI), has identified five genes that interact with Ras to cause metastasis.

Each of these “cell polarity genes” normally fills an important role in maintaining the orientation of the cell with regard to the inside or the outer surface of the body. The normal version of Ras, meanwhile, transmits signals that aid in development by controlling the rate at which various cells reproduce and differentiate. Although neither a mutation in a cell polarity gene nor a mutation in Ras leads to malignancy on its own, Xu and graduate student Raymond Pagliarini have shown in an animal model that when tumor cells have both mutations, they invariably produce metastatic tumors.

The scientists arrived at these findings by creating a genetic screen in Drosophila melanogaster, the fruit fly. If Drosophilaseems at first to be an unsuitable model for humans, it is only because our outer forms look so different. Inside we have a great deal in common: for instance, 70 percent of the disease-causing genes in humans also appear in the fruit fly. Xu and Pagliarini first used fruit flies with mutant Ras genes to create noninvasive tumors in developing larvae, then added other mutations to see whether the tumors become metastatic. Although only a handful of these combinations produced the results they were looking for, Xu and Pagliarini’s observations are likely to spur the development of new drugs for cancer treatment, targeting genes that collaborate with Ras to deadly effect.

As for Ras itself, this gene has been in the sights of pharmaceutical companies for some time now, and Xu points out that it still represents a good target for anti-cancer drugs. “Inactivating the tumor-producing effect of mutant Ras genes,” he says, “will likely be simpler than re-creating the tumor-suppressing effect of genes that are no longer normal, but mutated.”

As Xu sees it, “cancer is generally a late-stage disease—but in most of human history, longevity was much lower than it is now. People didn’t live long enough to get cancer.” What then was the original function of these genes? “We believe they are normally involved in regulating development, especially the size of cells and tissues, and ultimately the size of whole animals,” Xu says.

The most exciting aspect of Xu’s work on the metastatic partners of Ras is undoubtedly its clinical potential, but in Xu’s eyes this series of experiments offers another far-reaching benefit as well. “This work really showed the power of model organisms like fruit flies, because we can use them to do a lot of experiments that would not be possible in humans,” he says. It was this painstaking, gene-by-gene screening that allowed researchers to find the specific gene interactions that lead to metastasis, and thus to identify the drug targets that look so promising today.

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