Cells perform some moves you definitely shouldn’t try in yoga class. As immune cells hunt down invading microbes, for example, they contort themselves to fit into the narrow gaps between other cells. But they pay a price: Two new studies reveal that these feats of flexibility can burst the membrane that encloses a cell’s nucleus and damage its DNA. The results could ultimately enable researchers to design drugs to prevent cancer cells from migrating to new locations.
“It’s a very surprising discovery,” says biophysicist Ben Fabry of the University of Erlangen-Nuremberg in Germany, who wasn’t involved in the work. Fabry says he has been observing cells squeeze through confined spaces “for years but I had never noticed it.”
Watching cells twist and turn as they try to fit through small openings—sometimes less than a quarter the width of their bodies—“you almost feel pain for them,” says cell biologist Matthieu Piel of the Curie Institute in Paris. But because a cell is pliable, researchers had thought that these struggles wouldn’t cause any harm. The nucleus is stiffer than the rest of the cell, however, and it might not be able to take the stress. “We started to wonder if cells were damaging the nucleus” when they crawled through tight spots, Piel says. Coincidentally, across the Atlantic, biomedical engineer Jan Lammerding of Cornell University and his colleagues had begun wondering the same thing.
To find out, both groups observed cells traversing various kinds of narrow gaps. Lammerding’s team placed cancer cells and healthy cells on a miniature obstacle course (see video, above). The cells had been genetically modified so that they carried green or red fluorescent proteins inside their nuclei. When a cell slithered through a tight spot, the color leached into its cytoplasm, suggesting that the membrane that seals off the nucleus had burst. Piel and colleagues also noted leakage of molecules from the nucleus as immune cells and cancer cells similarly felt the squeeze. Both teams report their findings online today in Science.
Researchers had thought that healthy cells only opened the nuclear membrane just before they are about to divide. At other times, mixing the contents of the nucleus and the cytoplasm could be devastating. The cytoplasm contains enzymes that defend against viruses by destroying their DNA. If the nuclear membrane ruptures, these enzymes could gain access to the cell’s DNA. A tear in the nuclear membrane “is the worst thing that can happen to a cell and have the cell survive,” Piel says.
But a ruptured nuclear membrane wasn’t the only problem the squeezed cells had to cope with. Both groups determined that worming through narrow gaps damaged the cells’ DNA. The cells accrued double-strand breaks, a type of DNA injury that could spur them to die or become cancerous. Whether these breaks resulted from cells’ antiviral enzymes attacking their own chromosomes or from some other cause—such as the compression the cells endured–isn’t clear, Lammerding says.
Cells are able to live through the trauma because they quickly heal, the two groups found. They mend their fractured DNA, and a molecule known as the ESCRT III complex seals holes in the nuclear membrane. Repairs to the nucleus were under way less than 2 minutes after a rupture, and they were complete within 10 to 30 minutes, Lammerding and colleagues determined.
This nuclear and DNA damage both groups observed in the lab experiments could be widespread in our bodies because many of our cells in are on the go, says cell biologist Michael Sixt of the Institute of Science and Technology Austria in Klosterneuburg, who wasn’t connected to the study. “When they are moving they are constantly getting this ‘massage’” that can rupture the nuclear membrane. The work raises questions about how cells deal with the nucleus as they move, he says. “They can’t just push it around—they have to protect it somehow.”
The ability to repair breaches in the nuclear membrane could help immune cells survive, but it could also benefit cancer cells. Tumor cells that metastasize, or move to a new part of the body and start growing, are what kills most cancer patients. However, Lammerding’s and Piel’s groups showed that blocking DNA and nuclear membrane repair was fatal for cells that had been squeezed, suggesting that drugs that inhibit both processes could prevent cancer cells from metastasizing—although researchers might have to find ways to curb the damage to healthy cells. Cancer cells, Lammerding says, would be “killing themselves by moving through the tissue.”
(Video credit: Science)