A breast cancer cell. LRI EM Unit
If you’ve not heard of asparagine, you might be able to guess what this molecule is named after: the humble asparagus, because this veg – and a number of other foods – contains lots of the stuff.
Asparagine is an amino acid. These are the building blocks for proteins that keep our cells working. While asparagine is an important part of many different proteins in the body, it seems that the molecule also has a less desirable role, one that scientists think could be exploited to improve cancer treatment.
New research, funded by Cancer Research UK, shows that asparagine is critical for breast cancer to spread in mice, and the process might be shared in people. Blocking this amino acid in mice by cutting it out of their diet also hampered spread of the disease.
It could be that manipulating levels of asparagine in the body might be used as a way to boost a patients’ cancer treatment
– Prof Hannon
The researchers, publishing their findings in Nature, think that this could open up new treatment possibilities.
“There are many levels to this story,” says lead researcher Professor Greg Hannon, director of our Cambridge Institute.
“But it could be that manipulating levels of asparagine in the body might be used as a way to boost a patients’ cancer treatment.”
When a cancer spreads, or metastasises, it becomes more difficult to treat.
In order for this to happen, cancer cells need to break away from the original tumour, squeeze their way into blood vessels and make their way around the body, before escaping from the circulation and settling in a new location. New tumours that form in these sites are known as secondary cancers, or metastases.
Hannon and his team studied two different types of mouse breast cancer cells to learn more about this process. Their previous research showed that while these cells can escape the breast tumour and enter the bloodstream – becoming what are known as circulating tumour cells – their abilities to form secondary cancers differed.
“Despite both entering the blood, only one of these cell types makes it to other sites in the body,” says Hannon. “This research set out to look for differences between these cells.”
The team looked at the genes that were switched on inside each cell type, and found 192 that were more active in those with a greater ability to spread, called 4T1-T cells. When they then compared gene data with similar information from patient samples, the researchers found the same genes were more active in people with aggressive breast cancer.
The researchers then used molecular tools to switch genes off individually in 4T1-T cells and watched how this affected their spread in Petri dishes and mice. In both tests, switching off a gene called asparagine synthetase stopped the cells from spreading. As the name suggests, this gene is responsible for making asparagine in the body.
“Asparagine is a non-essential amino acid,” says Hannon. “Your body can make what you need.” This means we don’t have to rely on food as a supply of this amino acid, unlike some others.
The team then turned to two sets of tissue samples from breast cancer patients. Combing through genetic data they found that higher activity of the asparagine-producing gene was linked with breast cancer coming back, including in the lungs.
High activity of the gene was also linked to poorer survival in other cancers, particularly kidney and head and neck cancers, based on another set of patient data, says Hannon.
Each of the results together suggested that high asparagine levels might affect the ability of cancer cells to spread. So the researchers next tested the effects of changing asparagine levels in the lab in a number of ways.
Breast tumours in mice made of the 4T1-T cells were less able to spread when the mice were treated with a leukaemia drug that chops up asparagine. And the same result happened when the researchers simply fed the mice a low asparagine diet.
So far the story suggests that lowering asparagine levels blunts the ability of cancer cells to spread in mice, but doesn’t affect the original tumour. The researchers think this could be down to the amount of asparagine that is naturally found in different parts of the body. In both mice and people the team saw it was highest in breast tissue, while lowest in the bloodstream. So this could make circulating tumour cells particularly susceptible to cutting off its supply.
But what is it about asparagine that seems to be critical for the ability of breast cancer cells to spread? When cancer cells metastasise, they change their identity and become more like stem cells – the ‘blank slate’ cells that can move and develop into all the different cells our bodies are made of.
It transpires that the proteins required for this identity shift are rich in asparagine.
We showed that if we manipulate the availability of asparagine, we can change the character of the breast cancer cells
– Prof Hannon
“We showed in this study that if we manipulate the availability of asparagine, we can change the character of the breast cancer cells to become less like stem cells,” says Hannon.
While unproven, Hannon thinks this raises the possibility of using a similar approach in certain cancer patients to treat their disease.
“We’re starting to think about finding ways to complement existing treatments with this strategy,” he says. “It might be that patients could be given an asparagine-restricted diet in hospital alongside their primary treatment, as a way to reduce the long-term risk that their disease will return.”
This research is still in early stages, and doesn’t form the basis for DIY diets at home. But Hannon believes there’s potential.
“More and more reports are coming out that cancer cells have addictions to certain molecules,” he says.
“The difficulty is finding ways to study this in the lab that are relevant to patients.
“It’s a challenge, but I think it’s worth pursuing.”
Knott, S. R. V. et al. (2018). Asparagine bioavailability governs metastasis in a model of breast cancer. Nature. DOI: 10.1038/nature25465