Pack Mentality

What if we could stop cancer cells from playing follow-the-leader?

When cancer cells split off from a tumor to seed deadly metastases, they are thought to travel as clusters or packs, a phenomenon known as collective invasion. By finding ways to disrupt or destroy the leader cells in this process, Emory researchers hope to discover how to keep cancer from spreading.

Lung cancer cells making up an invasive pack have specialized roles as leaders and followers, which depend on each other for mobility and survival, the scientists reported recently in Nature Communications. The differences between leaders and followers—and their interdependence—could be keys for future treatments aimed at impairing or preventing cancer metastasis, says senior author Adam Marcus, associate professor of hematology and medical oncology at Winship Cancer Institute and the School of Medicine.

“We’re finding that leader and follower cells have a symbiotic relationship and depend on each other for survival and invasion,” he says. “Because metastatic invasion is the deadliest aspect of cancer, our goal is to find agents that disrupt that symbiotic relationship.”

Marcus and former doctoral student Jessica Konen 16PhD began by observing how a mass of lung cancer cells behaves when embedded in a 3-D protein gel. The cells generally stick together, but occasionally a few cells extend out of the mass like tentacles, with the leader cell at the tip.

“We saw that when the leader cell became detached or died unexpectedly, the followers could no longer move,” says Konen, now a postdoctoral fellow at MD Anderson Cancer Center. “In one example, we saw a leader cell come away from the rest, and then seem to realize that nobody was following. He actually did a 180 and went back to grab cells to bring with him.”

To study how the cells differ, Marcus and Konen developed a technique for marking the cultured cells with a laser, changing them from fluorescent green to red, and then isolating red cells. The patterns of genes turned on or off revealed that leader cells secrete more vascular endothelial growth factor, which appears to be important for pack formation because it is a mobility factor leaders provide followers. And in the absence of followers, leaders multiply at a slower rate and have more bulges of the cell membrane; contact with follower cells seems to alleviate these problems.

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