Science Snaps: how skin cancer spreads – the round or flat of it

We return with an image hot off the microscope – today, a team of our scientists from King’s College London have discovered how shape-shifting melanoma cells deploy different groups of enzymes to help them spread.

Imagine you’re walking on grass, glass or hot coals. How differently would you move on these surfaces?

Well, certain cells in our body face similar environmental obstacles, encountering many different ‘molecular grasses’ – collectively known as the ‘extracellular matrix’. And they respond to this world in different ways.

Last June, our scientists looking at melanoma – the most serious form of skin cancer – found that cancer cells can switch between being round and squishy (like the cells in red above) or flat and elongated, adopting the best shape to aid their escape from the tumour and helping them spread to other parts of the body.

The researchers compared round or flat melanoma cells

To visualise how this works, imagine you’re stuck in a busy crowd. Switching cell shape is similar to either squeezing and wriggling through smaller gaps or simply pushing through the crowd to create your own space.

Scientists already knew that the flat, elongated melanoma cells created their own space, releasing enzymes called matrix metalloproteinases (MMPs) and dissolving the molecular meshwork around them, freeing up some space to move into.

In contrast, the round cells were thought to be flexible enough to just squeeze through tight spaces and continue on their journey.

But today, a team of our scientists – led by Dr Victoria Sanz-Moreno – have published a paper in the journal Nature Communications showing that the round and squishy cells are more than just malleable – as well as squeezing through tight gaps it seems they too release digestive MMPs, potentially making their journey a little easier.

Mowing the ‘molecular grass’

So how did they discover this? The team grew two different types of melanoma cells in the lab – one group that were predominantly round and another group that were a mixture of round and elongated cells.

Round melanoma cells (red) dissolve the grey collagen matrix

When they analysed the arsenal of MMPs they released they found that the round cells were producing much higher levels of three particular MMPs – known as MMP-9, MMP-10 and MMP-13.

Next they grew the cells on a type of ‘molecular grass’ called collagen I. The round cells were much better at chopping up and clearing away the collagen I than the flatter cells.

You can see this in the image to the right – the round melanoma cells are in red and the tangle of grey fibres near the cells are the collagen I. Using a specialised microscopy technique, the team could illuminate the collagen that had been chopped up – shown as the cyan colour in our image.

They found that the collagen was more heavily chopped up near the round cells than the flat cells, resulting in more free space to move around in.

Round or flat?

The differences between the round and flat cells led the team to ask, what role might these different levels of MMPs be playing in controlling cell shape? And how might this help these cells move?

To answer this they focussed on MMP-9.

Looking at a whole range of melanoma cells they found that the more round cells there were, the more MMP-9 there was. And when they used a genetic trick to stop the cells from making MMP-9, a large number of the cells switched from being round to being elongated.

When the team looked at how effective the different cells were at burrowing into a block of collagen I (to mimic how cells might invade the tissue around a tumour), they found that the cells with MMP-9 production switched off were far less able to burrow than the flatter cells.

This suggests that these cells need high levels of MMP-9 to keep them round and help them spread.

What’s next?

In this latest study, our scientists have shown that it’s not just flat, elongated melanoma cells that use MMPs to move around. The next challenge will be refining how this process works and testing whether the same shape-shifting behaviour happens in people with melanoma and how we might be able to explore this for new treatments.

This study reinforces the idea that tumours are a highly complicated mixture of different molecules and cells, all with the potential to react differently to each other and even the world around them.

But it’s only through looking at these differences that we find the most unified way of beating them.
In this case it’s the molecular gardening that helps cells move, which is intimately linked to the deadly later stages of cancer that’s spread to other parts of the body.

In terms of melanoma this is really important. It’s the most serious form of skin cancer, with the potential to spread quickly and aggressively. So finding new ways to put the brakes on these cells is vital.

Nick

All images courtesy of Dr Sanz-Moreno and her team

Dr Sanz-Moreno is a funded fellow of our Women of Influence initiative – read more about the scheme here.

Reference

• Orgaz J.L, et al. (2014). Diverse matrix metalloproteinase functions regulate cancer amoeboid migration, Nature Communications, 5 DOI: 10.1038/ncomms5255