Anh Hoang Le, a PhD student at the Cancer Research UK Beatson Institute in Glasgow, studies two proteins that we know curiously little about: CYRI-A and CYRI-B.
“We have some hints that they might be involved in cancer, and it’s my teams’ job to find out if it’s true.”
Le has been growing batches of cancer cells in the lab that have one key difference: some can produce the CYRI proteins, while others can’t. He then looks for differences between the cells using tools similar to microscopes.
And so far, the most striking of these has been changes in cell shape, which can have an important effect on how the cell behaves.
“I have four different stains on these cells so you can see four different things. The nucleus is the round blue balls in the middle of each cell, which contains DNA. The cytoskeleton, which essentially is the skeleton of the cell, is in magenta. The yellow is a protein called ArpC2, and the green is a protein called integrin,” he explains.
The molecules aren’t usually those colours. Le sticks a different fluorescent dye to each molecule to make them glow. It’s a standard technique in cell biology if you want to look at things inside a cell. And it produces some beautiful images while you’re at it.
Supporting roles – integrin and ArpC2
Integrin, in green, has multiple jobs. But one of its most important roles is sticking the cell to its surroundings, like an anchor. It’s known to be key in deciding the shape of the cell. And it’s been linked to the spread of cancer cells around the body.
In an earlier experiment, Le found that when he removed the CYRI proteins from cells, they became stickier. But they also moved faster than cells with the CYRI proteins. As integrin is known to be involved in both these processes, Le decided to look at the location and amount of integrin inside the cells.
The image above shows a regular cancer cell on the left, and one that been engineered so it doesn’t produce the CYRI proteins, on the right.
“When I removed the proteins from the cell, it changes shape. And you can see that when they are present, the integrin is very spread inside the cell. But without, you can suddenly see all of those green stripes that align with the cell. So without the CYRI proteins, integrin is more prominent and is perhaps helping the cell to move.”
Another protein called ArpC2, marked yellow in the image, is also important in cell movement. The protein collects at the edges of the cell when it wants to move, which is what happens in cells without the CYRI proteins.
Overall, Le thinks CYRI-A and CYRI-B may be changing the distribution of integrin and ArpC2 inside cells, which leads to the change in shape. And this could trigger cancer cells to move.
Shaping up nicely
The shape of a cell is important because it indicates what the cell may be likely to do, whether that be multiply, move or die.
“The cell with the proteins has very spiky protrusions,” says Le. “Those spikes are called filopodia, which we think are for the cell to sense its environment.”
Cancer cells without the CYRI proteins have less obvious protrusions. In the right-hand image above, they’re the small bumps around the edge of the cell. “We call that lamellipodia, which we think is more for a cell to ‘crawl’,” says Le.
Le’s lab research suggests that if cancer cells lose the ability to make the CYRI proteins they may be more likely to move, which could be linked to cancer spread (metastasis). But it’s early days.
“There is a lot of debate,” warns Le. “So it is difficult to firmly say that if you have more lamellipodia the cell is going to metastasise, because inside the actual cancer there are a lot of interactions and factors that we don’t have enough knowledge about yet.”
According to Le, which structures are important for cancer to progress may actually differ depending on the cancer type.
For now, Le’s work is helping uncover the roles of these mysterious proteins in cancer. And he’s produced some great images along the way.
“My favourite? I think it’s the ‘fan-shaped’ one. Because, compared to the spiky one, it gives you a striking look at how different the cell shape is when the proteins are not there.”
Fort et. al. (2018). Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. Nature. DOI: 10.1038/s41556-018-0198-9