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A group of NIH researchers have just discovered that healthy human cells moving through a three-dimensional matrix propel themselves quite cleverly: the nucleus acts as a piston, increasing pressure at the cell’s leading edge and causing a protrusion that drives the cell forward. This is very different from the way scientists thought cells moved, which they figured out partly from watching cancer cells on a two-dimensional Petri dish surface.
“We think it’s actually a really common type of mechanism that’s used in the body by multiple cell types,” said Ryan Petrie, lead researcher on the project. “It just really hasn’t been appreciated before because you need the appropriate three-dimensional model systems to study this type of cell movement.”
For years, researchers have known that cancer cells move forward via flat, lamellipodial protrusions. The protrusions extend outward, grab the surface, and the rest of the cell follows. Researchers assumed normal human cells moved in the same way.
But in 2012, Petrie, a postdoc in Kenneth Yamada’s lab at the NIH, discovered that when human fibroblasts are put into a special, fibroblast-derived, cross-linked three-dimensional matrix, they switch to a different means of transport: cylindrical protrusions they dubbed “lobopodia” (1). Petrie and his group didn’t know how the lobopodia formed, or why, but they hypothesized that an increased internal pressure may play a role, since they observed “blebbing”—bulges in the plasma membrane.
The team used a microelectrode coupled to a micropressure system to measure the internal pressure of the human fibroblasts in front of the nucleus. It was very high, much higher than cancer cells in the same matrix. But when they measured the pressure on the other side of the nucleus, it was much lower. They introduced a photoactivatable green fluorescent protein into the cytoplasm of the live cells and saw that the protein significantly slowed as it tried to move around the nucleus (2).
“It really got us thinking about, well, how could the pressure be generated in the cells?” said Petrie. “Because the dividing line was the nucleus, between these high and low pressure zones, this is when we began thinking about the nucleus as a piston, actually generating the pressure.” Using confocal microscopy, they saw the nucleus being pulled forward by the actin-myosin machinery.
“When we look at how these untransformed normal fibroblasts migrate and use lobopodia in this physiological matrix, we now have something to compare to cancer cells,” Petrie said. “Knowing much better what is actually wrong with them, maybe we’d have a better sense of how to fix them or how to more efficiently block their migration. That’s really desirable because if you could somehow specifically block the inappropriate movement of cancer cells then you could reduce or prevent metastasis.”
1. Petrie, R.J., et al. 2012. Nonpolarized signaling reveals two distinct modes of 3D cell migration. Journal of Cell Biology. 197(3): 439-55.
2. Petrie, R.J., Koo, H., and K.M. Yamada. 2014. Generation of compartmentalized pressure by a nuclear piston governs cell motility in a 3D matrix. Science. 345(6200): 1062-1065.
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