ABOVE: Cow trophoblasts (green) invade a layer of human stromal cells (black), which may also be susceptible to metastasizing cancer cells.

KSHITIZ ET AL., NAT ECOL EVOL

EDITOR’S CHOICE IN CANCER BIOLOGY

The paper

Kshitiz et al., “Evolution of placental invasion and cancer metastasis are causally linked,” Nat Ecol Evol, 3:1743–53, 2019.

The study was conceived like a cliché joke: an evolutionary biologist, a cell-signaling specialist, and a cancer researcher walk into a happy hour at Yale University. The conversation turned to mammalian tumors, and how it was common to see horses in Austria and cows in India with prominent tumors that rarely killed the animals.

It turns out that horses and cows have something else in common. “Interestingly, in the same animals, the pregnancy is very different from human pregnancy,” says the University of Connecticut Health Center’s Kshitiz, the cancer researcher, who uses a single name. Placental cells in ungulates don’t burrow into the uterine lining early in pregnancy as they do in apes and many other mammals.

The researchers were not the first to draw a connection between cancer severity—specifically, whether the tumors metastasize to other locations in the body and become more deadly—and placental invasion. But they wondered if the key to that link was the action not of the invading cells, but of the tissue that was under attack. Together with colleagues, the trio cultured layers of human or bovine endometrial stroma cells and tested their resistance to invasion by placental cells from both species and by a melanoma cancer cell line. “The difference between cow and human was just like day and night,” Kshitiz says. “The cow cells will resist invasion; the human cells will . . . not only not resist, but may even assist invasion.”

“I think the most striking feature of this paper is that they show that it’s not really the way in which the cancer cells behave that’s different, but it’s really the fibroblasts—the stromal cells—how they respond to the cancer cells,” says Karuna Ganesh, an oncologist and cancer researcher at Memorial Sloan Kettering Cancer Center. The finding suggests, she says, that healthy fibroblast tissue could be targeted by therapeutics with the aim of halting metastasis. That’s a possibility Kshitiz’s lab is already exploring in follow-up work.