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Invading cells bulge to get through barriers

Scientists have figured out how invasive cells deploy a trick to break through tissues. The findings may help explain how cancer spreads to other parts of the body.

In a new study, 3D time-lapse imaging of cellular “break-ins” in the transparent worm C. elegans reveals a fleeting, yet key structure in action. A single protrusion bulges out from the cell surface, wedges a hole through the protective layer that separates the cell from other tissues, and swells until the breach is wide enough for the entire cell to squeeze through.

The discovery could point to new ways to prevent metastasis, the spread of cancer cells which typically makes the disease deadlier and difficult to treat.

Most cells in the body stay put. But from time to time, cells trespass into other tissues, says David Sherwood, a biology professor at Duke University and lead author of the paper in Developmental Cell.

The ability of cells to break and enter is critical for many normal processes, such as when the placenta attaches to the uterus during early pregnancy, or when immune cells push their way through blood vessel walls to get to sites of injury or infection.

Cell invasion is hijacked during metastasis, when cancer cells leave their original tumor sites and spread to other parts of the body.

invading cell gif
A time-lapse video of an invading cell in the worm C. elegans shows a fleeting protrusion that may help explain how cancer spreads. (Credit: Kaleb Naegeli/Duke)

After the ‘invadopodia’

To spread, a cell must first penetrate a sheet-like mesh of proteins and other molecules called the basement membrane, which supports and surrounds tissues like a Kevlar wrapper.

One of the first steps in this breakthrough process was recognized 30 years ago. The basement membrane is too dense to slip through, so invading cells begin by pushing out tiny “feet” many times finer than a human hair, called invadopodia. These piston-like projections pop out of the cell surface every few seconds and then retract, until one punches a tiny hole in the basement membrane. What happens after the initial breach, however, was less clear.

The new study identifies a second structure that takes over after invadopodia make the first puncture.

“Migrating cells have a remarkable repertoire of invasion tactics. This study reveals another trick up their sleeve.”

Researchers used a camera attached to a powerful microscope to take pictures of invading worm cells every five minutes for up to three hours and tracked a specialized cell called the anchor cell, which breaks through the basement membrane that separates the worm’s uterus from its vulva to connect them so the worm can lay eggs.

They discovered that the C. elegans anchor cell accomplishes this task with the help of a single large protrusion that wedges into the tiny hole created by the invadopodia, like a foot in the door. As the protrusion enlarges, it shoves the basement membrane aside and expands the existing hole.

Rather than stretching like a balloon, the protrusion inflates by adding to the cell membrane from within. Tiny sacs inside the cell called lysosomes concentrate at the breach site. Once there, they fuse with the cell’s outer membrane, increasing its surface area. As the protrusion swells, a protein called dystroglycan clusters at its base to keep the bulge from deflating.

The pushing forces “clear a path for invasion similar to the way a balloon catheter inflates to open an artery,” Sherwood says. Within a half hour it contracts, leaving behind a hole wide enough for the cell to move through.

To make the protrusion, the cell relies on a chemical cue called netrin and its receptor to direct lysosomes to the site. High netrin levels have been linked to metastasis in numerous human cancers, which suggests the mechanism the researchers found is a common feature of invasive cells, Sherwood says.

Failed drugs

The findings might also explain why drugs designed to block the spread of cancer by targeting invading cells have failed.

Several proposed treatments work by inhibiting enzymes called metalloproteinases that dissolve the basement membrane. The reason such therapies have had limited success in clinical trials, may be because they ignore a pivotal player in cancer progression—these inflatable protrusions that bulge out from the tumor cell and push the basement membrane aside.

‘Assassin’ molecules drive cancer cells to self-destruct

Figuring out how to block the netrin pathway and prevent cancer cells from putting out new protrusions might deprive them of a critical tool they use to spread, Sherwood says.

“Migrating cells have a remarkable repertoire of invasion tactics. This study reveals another trick up their sleeve.”

The American Cancer Society, the National Institutes of Health, and the National Institute of General Medical Sciences supported the work.

Source: Duke University

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