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Different shaped cancer cells. Credit: Dr Chris Bakal

Appearance matters when it comes to cancer cells.

Long before modern medicine, doctors and philosophers learnt about cancer by simply looking at tumours taken from people who had died. This was coined pathology, which loosely translates to the study of disease.

Fast-forward to the 1800s and doctors began inspecting tumours removed during surgery more closely, thanks to the invention of microscopes. They soon realised that cells in tumours look very different from healthy tissue and they could even tell apart different types of cancer.

Studying samples of tumours (biopsies) in this way still plays a vital role in diagnosing cancer patients today. It reveals information about the type of cancer and how aggressive it’s likely to be, which helps doctors offer patients the best treatments.

But until now it has remained a mystery as to why the shape of cancer cells is so good at predicting the disease’s behaviour.

In a study published today in the journal Genome Research, researchers led by Dr Chris Bakal from The Institute of Cancer Research, London and funded by Cancer Research UK, reveal some key information about this strong link between cancer cell shape and patients’ outlook.

This in-depth account of the genes behind cancer cell shape, and how they’re linked to the likelihood of a tumour spreading, could help develop new treatments that make cancer less aggressive and easier to destroy with other therapies.

And Bakal’s team has produced a map to help navigate these next steps.

Constructing the map

The team started building a map using huge amounts of data from breast cancer cells grown in the lab. Some of these breast cancer cells grow aggressively, others more slowly.

They had images of more than 300,000 individual cells that were matched to genetic data showing how active different genes were.

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“We looked at features including the size of the cells, how closely cells were packed together, how much contact they have with their neighbours, and whether the outside of the cell is smooth, ruffled, or spiky,” says Bakal. “And then we matched it to their genetic data.”

The team combined the information into a map, much like the London Underground map, with the cells’ appearance forming the stations and the genetic information revealing the tube lines connecting these shapes.

Bakal_map

The team’s map that connects genetic data with the shape of cells. Credit: Dr Chris Bakal

“We already had lists of genes where there are significant differences between aggressive and more slow-growing breast cancers,” Bakal says. “But we were surprised that we found so many of these genes play an important role in determining cancer cells’ shape.”

On closer inspection, the activity of many of these genes was already known to affect cell shape, for example genes that are needed to make cells’ internal ‘skeleton’. But there were also some surprises.

“We found some unexpected results, for example some genes that matched with very rounded cells are involved in processes that happen in the mitochondria – the energy-producing machinery in cells,” says Bakal.

What came first – the genes or the shape?

The next thing the researchers wanted to know was whether cell shape was affecting the levels of genes, or whether those genes being switched on or off was controlling cell shape.

“We had a classic chicken and egg situation,” Bakal says. “A huge data set from the Broad Institute in the US helped us answer this question.”

We discovered that shape was having the bigger effect on genes, rather than the other way round

– Dr Chris Bakal

By analysing publically available data, the researchers could figure out which way information was flowing in their map.

“We discovered that shape was having the bigger effect on genes, rather than the other way round,” says Bakal. “And this could be relevant when it comes to thinking about potential new treatments.”

Cells can sense their environment and the forces around them that push, pull, stretch and squash them.

“We know this environment is important because tumours like their surroundings to be stiff. This stiffness helps cancers grow, spread and resist treatments. And it turns out that the stiffness of their surroundings also affects the shape of cancer cells and in turn changes their genetic profile.”

One of the genes central to the map is called NF-kB. “The close association between highly active NF-kB and aggressive cell shape is really interesting,” says Bakal, “because there are rarely mistakes in this gene in cancer. The gene itself often isn’t faulty in solid tumours, but shape changes can alter its activity, and help the cancer spread.”

On course for potential new treatments

Doctors use pathology data and the shape of cancer cells to diagnose cancer because it gives them reliable information on how aggressive the cancer is likely to be. Bakal’s team wanted to know if the genetic map they’d created could predict the same outcomes.

“We compared our shape-based genetic map, drawn up from lab-grown cells, with genetic and medical information from women who’ve had breast cancer,” says Bakal.

The researchers used data from our METABRIC study, which includes genetic information and clinical records from nearly 2000 women with breast cancer.

“We found that our gene profiles could be used to predict how aggressively breast cancers behaved, telling us the genetic map we’d created was relevant to cancer in the clinic too,” Bakal says.

This is the first glimpse into why – at the genetic level – the ancient practice of studying cells’ shape is a tell-tale sign of a cancer’s behaviour. And Bakal hopes their genetic data map will be mined for information leading to new treatments.

For example, researchers are studying whether drugs that stop cancer cells producing a molecule called LOX can be effective at treating some types of cancer. The LOX molecule works by making the tumour’s surroundings stiffer, “and this will probably change cancer cells’ shape and genetic profile as we’ve seen in our studies of breast cancer,” says Bakal.

As well as drugs targeted to the tumour’s environment, this research could lead to new drugs that change the shape of the cancer cells, re-routing the activity of their genes and hampering their ability to spread.

“Many of the chemotherapy drugs we use today, like paclitaxel, change the shape of the cells,” says Bakal. “Now we’re getting to the bottom of what’s happening at the genetic level, there’s scope to make shape-altering drugs more potent.

“Changing the shape of cancer to make it less aggressive could be effective in combination with other therapies – giving them a better chance to work.”

It’s early days yet, but this research is a big step forward in understanding a fundamental, age-old mystery: why the shape of cancer cells is so important in predicting how the disease will behave.

Emma

  • All images featured in this post were provided by Dr Chris Bakal