A chemical ‘breadcrumb trail’ helps melanoma spread

From flashing green men to high-pitched beeping, when we cross the road there are plenty of signals to help us.

But if these cues fail, it can cause us to hesitate, rush, stop-start or randomly change direction. And while the picture’s a little more complex in our bodies, our cells too must be aware of particular signals that point them in the right direction.

And much like a broken traffic light, changes in how cells perceive these triggers can have serious consequences. Nimble tumour cells help cancer spread rapidly – something that’s particularly true in melanoma – a cancer that can be difficult to treat, especially if it’s diagnosed at a more advanced stage.

Chasing down the molecules that give melanoma cells the green light to spread are Professor Robert Insall and his team at the Cancer Research UK Beatson Institute in Glasgow.

And today, they’ve published their latest findings in the journal PLOS Biology, showing how a chemical signal may help melanoma cells navigate the world around them.

Chemical attraction

Insall and his team, including lead researcher on this study Andrew Muinonen-Martin, are interested in tracking the precise movements of tumour cells, something they believe is vital for finding new ways to stop the deadly late stages of cancer.

The cells generated their own LPA gradient

Melanoma cells move with precision to escape the confines of the tumour and spread around the body. This prompted the team to ask what was unique about the type of cell movement these tumour cells are using to guide their journeys.

The researchers focussed their attention on the chemical ‘breadcrumb trails’ responsible for movement known as chemotaxis – a process where the direction a cell moves in is dictated by the relative levels of a particular chemical in its surroundings:  cells travel from where there isn’t very much of it, to where there’s a lot, or vice versa (something known as a ‘chemical gradient’).

Many types of cancer cell, including melanoma cells, use chemotaxis as a way of spreading around the body. But the exact origin of these gradients, and the molecules involved, is still shrouded in mystery.

To find out more, the team filmed melanoma cells moving in the lab – and made a surprising discovery. The cells were able to find their way without the researchers setting up a chemical trail for them to follow. And the more cells they used in their experiments the more efficient they became at moving in a precise direction.

So what was providing this cue to move?

Microscopic ‘footsteps’

In a meticulous set of experiments, the team showed that the melanoma cells were in fact breaking down a chemical signal found in the nourishing soup in which they were growing.

By breaking down this as-yet unknown signal the cells were producing their own chemical gradient – put simply, there will always be a bit more of the chemical a few microscopic ‘footsteps’ away, tempting the cells to keep moving in that direction.

But what was the mysterious molecule directing these cells?

The team painstakingly eliminated different options, ruling out a number of important signals – called growth factors – that are known to help cells grow and move.

Eventually, they landed on another important signalling molecule called lysophosphatidic acid, or LPA for short.  When the cells were treated with LPA they moved with unprecedented accuracy, but if the researchers blocked the cells’ ability to ‘see’ the signal they lost their sense of direction (you can watch clips of these experiments in this video).

This told the team that the LPA gradient was acting much like a molecular sat-nav, guiding the melanoma cells on their journey. Next they confirmed that it was indeed LPA that the cells had been consuming from their growth medium in the initial experiments, providing compelling evidence that LPA gradients may be an important trigger for melanoma cells to spread.

What’s next?

Important questions remain – where’s the LPA coming from? And are there similar processes at play within the 3D world of a tumour?

Initial studies in mice with melanoma show that these LPA gradients do exist beyond the Petri dish, and may provide the trigger for cells to leave the tumour and spread around the body.

The team found that in mice, LPA levels were relatively low within the tumour itself, increasing around the edges of the tumour, and peaking in the tissues immediately beyond the melanomas.

The implications of this could be big. As the team concludes in its paper, this suggests that the melanoma could be responsible for its own spread by producing and following its own LPA gradient.

But, as Insall points out, there’s still a lot more work to be done. “The next step will be to find how the melanoma cells break down the LPA molecules to see if this sparks ideas for new ways to stop the cancer from spreading,” he told us.

Melanoma rates are five times higher than 40 years ago, with more than 13,000 people diagnosed each year in the UK, so finding ways to stop it spreading is of huge importance.

By piecing together this chemical breadcrumb trail, our researchers are one step closer to showing melanoma a red light.

Nick

A version of this post also appears on the Guardian Science blog network.

Reference

• Muinonen-Martin, et al. (2014). Melanoma Cells Break Down LPA to Establish Local Gradients That Drive Chemotactic Dispersal. PLOS Biol. DOI: 10.1371/journal.pbio.1001966

Images

• Breadcrumb image by Kat Selvocki, licensed under a CC-BY-NC-ND-2.0 license via Flickr
• Pacman image by bm.iphone, licensed under a CC-BY-2.0 license via Flickr