Image from Dr Erik Sahai from the Crick - shows melanoma cells and extracellular matrix (white) <prop id="gamma-green" type="floa
This entry is part 11 of 30 in the series Science Snaps
Drug resistance is a big problem, particularly for advanced melanoma.
People with melanoma respond well to a new generation of targeted cancer drugs. And landmark research from our scientists paved the way for one of these drugs, called vemurafenib (Zelboraf).
But the sad truth has been that in many cases, the cancer cells will eventually stop responding to these drugs and the disease will come back.
Understanding the ways in which melanoma cells develop this resistance is a big challenge. But researchers from across the globe are piecing together this complex picture, uncovering an array of cellular escape routes and proposing ways to block them.
Now, Dr Erik Sahai, and his team funded by us at the Francis Crick Institute, has uncovered a new route to resistance.
Publishing their findings in the journal Cancer Cell, the researchers – working with Professor Richard Marais’ team at the Cancer Research UK Manchester Institute – shed light on how the environment around a melanoma cell may play a role in drug resistance and, crucially, offer a potential new way to stop it.
A place to hide
The image above shows brightly-coloured melanoma cells nestled among a wiry cobweb of white fibres.
These fibres are made of collagen – an important protein that forms part of the environment around a cell, called the extracellular matrix.
But just as a cobweb provides a safe home for a spider, the new study shows how the extracellular matrix may provide a ‘safe haven’ for melanoma cells and encourage resistance to treatment.
The melanoma cells have been engineered to produce a fluorescent sensor that tells the researchers whether a key set of signals that help the cells grow are switched on or off.
“Warm, red colours indicate high levels of signal activity,” lead researcher, Dr Eishu Hirata, tells us. “Colder, blue colours show lower levels of activity,” he adds.
These cells have been treated with a drug that targets melanoma cells carrying a fault in the BRAF gene that causes them to survive and grow uncontrollably. BRAF switches on a series of important growth signals called the ERK pathway. “If the drug is effective, the colour turns into blue, but many cells in this image retain red colours, indicating that the cells are not affected by the therapy,” Hirata adds.
So how does a drug treatment that’s initially successful in killing cancer cells slowly become something that cancer cells can tolerate?
A deadly support network
Working with experimental laboratory models of melanoma the researchers found that drug resistance only appeared when the cancer cells were grown within the extracellular matrix and among other supporting structural cells.
These specialised support cells – called melanoma associated fibroblasts – responded to the drug treatment by twisting and shaping the extracellular matrix and laying down new protein fibres at the same time.
The team found that this refreshed network acts as a ‘safe haven’ for the cancer cells, switching on a different set of signals inside the cells that reactivates the ERK pathway – and allows the cancer cells to grow again.
Switching the cell signals back on via this alternative escape route means the cells can withstand the treatment, glowing orange and red again instead of the cooler blue colours.
The next step was to find a way to halt the resistance.
The right combination
Following a meticulous set of experiments the team found that the escape signal was controlled by another important protein called FAK – we’ve written about FAK before.
The researchers reasoned that if they could switch off the FAK escape signal at the same time as the BRAF signal, then the cancer cells would be unable to become resistant to the treatment.
Crucially, drugs that target FAK are already being developed as potential cancer treatments on their own. These drugs are still in the early stages of development, but when the researchers combined an experimental FAK drug with the BRAF treatment the cancers cells stopped growing and started to die.
This was a striking result, and offers important early evidence that combining these two treatments could help control the growth of a melanoma for longer than just using the BRAF treatment alone.
From control to cure
While the combined treatments stopped the tumours from growing in the team’s lab models, the tumours didn’t go away completely – put simply, the treatment wasn’t a cure.
But the findings offer a potential window for further research to find additional treatments that could push this response from control to cure. And important studies like this one lay the ground work for what could go on to become clinical trials in people with melanoma.
It’s only by studying melanoma cells alongside the surrounding ‘supportive’ healthy cells that we’ll truly understand the best treatment approaches to test in trials.
And by peering inside this world that surrounds a tumour, Sahai, Hirata and the rest of the team are leaving melanoma cells with no safe place to hide.
- To find out more about how BRAF-targeting drugs work, watch the animation below:
- Hirata, E. (2015). Intravital Imaging Reveals How BRAF Inhibition Generates Drug-Tolerant Microenvironments with High Integrin β1/FAK Signaling Cancer Cell, 27 (4), 574-588: 10.1016/j.ccell.2015.03.008
Featured image courtesy of Dr Erik Sahai, Francis Crick Institute
- Introducing our Science Snaps series
- Science Snaps: capturing the immune system and cancer
- Science Snaps: a sea of cells
- Science Snaps: why aren’t flies as big as hippos?
- Science Snaps: designer drugs
- Science Snaps: how skin cancer spreads – the round or flat of it
- Science Snaps: what can fluorescent fish teach us about skin cancer?
- Science Snaps: peering inside an expanding lymph node
- Science Snaps: Sir Henry Morris and the ‘anonymous Gentleman’
- Science Snaps: the art and science of cancer, the universe and everything
- Science Snaps: exposing melanoma’s ‘safe haven’ to help tackle drug resistance
- Science Snaps: divide by two
- Science Snaps: bridging the gap between nerve repair and cancer spread
- Science Snaps: prioritising the gene faults behind bowel cancer
- Science Snaps: switching T cells on – size matters
- Science Snaps: how knowing the shape of cancer cells could improve treatments
- Science Snaps: leukaemia cells are born to run
- Science Snaps: understanding where breast cancer stems from
- Science Snaps: fixing a cellular ‘antenna’
- Science Snaps: mapping cellular ‘stars’, one molecule at a time
- Science Snaps: a fly on the wall of cancer research
- Science Snaps: how nappy technology is helping us see cancer more clearly
- Science Snaps: digging for clues on how bowel cancer starts
- Science Snaps: spotting lung cancers’ ‘crime hotspots’
- Science Snaps: revealing a potential new marker for aggressive prostate cancer
- Science Snaps: seeing the effects of proteins we know nothing about
- Science Snaps: solving the mystery of an oddly-shaped tumour
- Science Snaps: targeting cancers’ surroundings
- Science Snaps: stopping cancer in its tracks
- Science Snaps: rearranging our understanding of the cancer genome
Robin Abu Ghazaleh April 15, 2015
The old “seed and soil” hypothesis of cancer prompted thought into the role of the environment in initiation and nurture of a tumour, but what is described here extends the idea. Similar insights have occured in microbiology with the realisation that mixed bacterial communities live within a matrix on surfaces without and sometimes within our bodies to give rise to very different properties of drug sensitivity than those observed in the laboratory.