Melanoma, hooves, and the uterus

Melanoma is often fatal in humans, particularly when it metastasizes, spreading from the skin to other tissues. Yet Lipizzaner stallions, the famed Viennese show horses, frequently develop skin cancer with no ill effects, in large part because the cancer tends not to spread in these horses. Since hearing about the melanoma-resistant horses, Günter P. Wagner, Ph.D., an Austrian native himself, has been trying to understand why. The answer, he found, relates to the evolution of mammalian pregnancy.

In many mammals, including humans, says Wagner, the fetus, via its sac-like placenta, invades the wall of the uterus, or implants, in much the same way that cancer metastasizes and invades new tissues. The hoofed mammals in which skin cancer does not metastasize—including horses, cows, and pigs—are also those species in which the fetus does not implant, and Wagner believes that this is no coincidence.

“If we investigate in cows or horses or pigs or whatever and see how they keep out invasive cell types—either the trophoblast, the placenta, or cancer cells—we may learn how to treat or contain or make less aggressive cancers in humans,” Wagner says.

Wagner, the Alison Richard Professor of Ecology and Evolutionary Biology, with a secondary appointment in the Department of Obstetrics, Gynecology and Reproductive Sciences, established his lab at Yale in 1991 in the biology department at 165 Prospect Street. When West Campus opened 10 years ago, Wagner was the first investigator to move his lab to the new enclave, which promised myriad interdisciplinary opportunities. As a member of West Campus’ Systems Biology Institute and the new Cancer Systems Biology @Yale program, which bring together researchers from different disciplines to work on common problems, Wagner draws on the diverse expertise of his collaborators as he explores the pregnancy-cancer link.

Other researchers had proposed that throughout the evolution of pregnancy, the aggressiveness of the fetus from a given species, like the strength of a bulldozer, determined the extent to which it invaded the uterus. Humans, for example, have invasive pregnancies: the fetus burrows into the lining of the uterine wall. Horses, cows, and pigs, on the other hand, have noninvasive pregnancies: the fetus contacts the uterine wall but does not burrow through it. Cow, pig, and horse fetuses, therefore, should be less aggressive than human ones. Wagner, however, says that the fetuses of hoofed mammals do not invade the uterine wall “not because the fetus became less aggressive; it’s because the mother found a way of keeping [the fetus] out.” It’s less the force of the invading fetus and more that of the uterus opposing the invasion that determines how far the fetus gets.

In collaboration with Andre Levchenko, Ph.D., director of the Systems Biology Institute and the John C. Malone Professor of Biomedical Engineering, the Wagner and Levchenko labs demonstrated how the uterine lining, the endometrium, fights the invading fetus. To simulate fetal invasion, the researchers set up placental cells to move along tiny grooves fabricated in the Levchenko lab as they pass through endometrial cells. Following the so-called nanogrooves, each one about 400 nanometers wide—about one-hundredth the width of a human hair—the cells move in a straight line, and researchers can easily measure their invasive progress. “That’s the basis for us being able to measure different rates of invasion that are going on,” Wagner explains. The result? Human placental cells travel farther through human endometrial cells than they do through bovine endometrial cells—cow cells are resisting the invasion.

The skin cells of pigs, cows, and horses, Wagner hypothesized, resisted melanoma metastasis in the same way that their wombs resisted fetal invasion. But what defenses could the skin and the uterus share? Both the endometrium and the skin contain cells called fibroblasts, and throughout the evolution of mammals, Wagner found, the fibroblasts in these two locations evolved together, such that as the uterus began to resist fetal implantation, so the skin began to resist melanoma metastasis. Nanogroove experiments supported the hypothesis: skin fibroblasts from cows resist melanoma invasion better than those from humans.

In experiments with bovine melanoma cells, Wagner collaborates with another West Campus researcher, Sidi Chen, Ph.D., assistant professor of genetics in the Integrated Science and Technology Center. Cow melanoma cells are hard to come by, so “we have to make them ourselves,” Wagner says. Chen uses gene editing techniques to rewrite the genetic code of cow melanocytes and make them cancerous. “Our goal is to grow healthy melanocytes in the lab, and then we ask Chen to make them into tumor cells so that we can study cow melanoma cells,” Wagner says.

To see whether human skin fibroblasts could be coaxed to resist invading melanoma, Wagner, in collaboration with the Levchenko lab, is modifying human skin fibroblasts to make them more like fibroblasts from cows. So far, modified human cells are better able to resist melanoma invasion than their unmodified counterparts. “This is still preliminary, but promising,” says Wagner.