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Cellular scavengers: How breast cancers ‘eat’ their support systems when they need nutrients

Jacob Smith
by Jacob Smith | Analysis

17 January 2024

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Breast cancer cells taken as part of a biopsy shown under the microscope
Shutterstock - David A Litman


In breast cancers, dense tissue surrounding a tumour is often an indication of poor prognosis. 

That density is caused by a tight network of cells and molecules like collagen in the tumour’s extracellular matrix (ECM), part of the tumour microenvironment. 

You might have heard us talk about the ECM before. It acts like a scaffold that provides a tumour with the structural support it needs to grow. 

But there’s a catch to having this dense support system. It makes it difficult for tumours to grow blood vessels, which limits their blood supply. 

That poses a problem. Our blood flow is how we deliver vital nutrients like oxygen and sugars to our tissues. A limited blood supply means a limited supply of nutrients. Without nutrients, the tumours will starve. 

So, to survive, cancer cells need to be able to adapt to find a new food source, and fast. 

Thinking fast

Previously, research has shown that when pancreatic cancer cells lack certain amino acids, the building blocks we need to make proteins, they can absorb proteins from their surrounding environment.  

Then, they break them back down into amino acids, which they can use to make energy by utilising special chemical pathways. 

That piqued the interest of a group of researchers at the University of Sheffield. They thought, if pancreatic tumour cells can absorb surrounding proteins to use as a source of amino acids, maybe breast cancer cells are using the dense ECM as a source of protein in a pinch.  

“Cancer cells get so few nutrients from the blood, you’d think they can’t grow,” says Dr Elena Rainero, who led the Cancer Research UK-funded team. 

“But since they are still growing, there must be other ways in which they can obtain enough food.” 

“Our idea was that maybe the cells can use their matrix, this scaffold around them, as a source of nutrients because it’s composed of proteins, and proteins can be broken down.” 

As the ECM provides the tumour with support, breaking it down to use for food might sound counterintuitive. But desperate times call for desperate measures. 

A modified metabolism

To put this idea to the test, they grew groups of breast cancer cells in the lab, along with the molecules that you’d usually find in the ECM.  

They then provided these groups of cells with different levels of nutrients. Some were given an unlimited supply of glucose, the sugar our cells use to make energy, and amino acids, whilst others had restricted amounts, mimicking the environment they’d grow in in the body. 

And they found that the cells were doing what cancer cells do best: adapting.  

Even in low nutrient conditions, the cells were able to grow, albeit not as quickly as the cells with full access to nutrients. 

“Once we found that, we wanted to understand how the cells do it,” says Rainero. 

“Is it because they are touching the matrix and that activates something inside the cells? Or is it because the cells are feeding on the matrix? 

“When we looked into that, we found that the cells are actually able to take parts of the matrix in and digest them.” 

That answered one question but raised another. If the cells were using something other than glucose to make energy, they must have modified their metabolism somehow.  

So, what did they change? 

Bacterial microbiome mapping. Orange lines making connections and overlapping each other.

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The intermediate 

To find out, they grew cancer cells with and without the ECM present, and looked at what was going on inside the cells. 

They looked for what’s called intermediates, molecules that are produced midway through a chemical pathway before they’re made into the final product.  

If a cell is using a certain unconventional pathway, there will be a lot more of the intermediates of that pathway present in the cell. Therefore, if you can identify the intermediates, you can identify the pathway that cell is using. 

In the cancer cells grown with the matrix present, they found a lot of an intermediate molecule called fumarate, which wasn’t there in the cells grown without the matrix. 

And fumarate was the missing puzzle piece. 

The presence of fumarate told the researchers that these cells were using an amino acid called tyrosine as a nutrient source. And to use tyrosine, the cells must be using an enzyme called HPDL. So, that solved one part of the mystery. 

But one of the most important findings of this study isn’t what they saw. It was what they didn’t see. 

A unique process

As well as the cancer cells, the team also grew normal breast cells with varying levels of nutrients, along with the proteins from the ECM. That showed them that in low nutrient conditions, the normal cells couldn’t survive.  

We know that under some conditions where certain nutrients are scarce, normal breast cells can absorb a large protein called laminin and break it down to use as a source of amino acids.  

But while these healthy cells can use some alternative food sources when push comes to shove, this research shows that they can’t use ECM components specifically. Only cancer cells can do that. 

And that means there’s an opportunity for intervention. 

Because normal cells can’t metabolise tyrosine, if we can block that pathway by blocking HPDL, we can prevent cancer cells from doing it without harming other cells.  

And even better, there are existing drugs that can block HPDL, including one that’s already approved for use in other diseases. 

Rainero and her team now want to investigate the use of these drugs in animal models of breast cancer to test their efficacy. 

Beating cancer sooner

Simply stopping cancer cells metabolising these amino acids isn’t going to be a silver bullet. 

“Cancer cells are very adaptable,” Rainero explains. “So, if you block this one way of them growing, it’s highly likely that with time, they will just readjust and find another way. And it’s only the most aggressive cancers that can feed on the matrix like this. 

“My expectation is that this will probably lead to a combination approach.” 

“So, if we can use a drug to stop the cells adapting in this way alongside a conventional treatment to kill them, that’s more likely to be effective.” 

But silver bullets aside, a combination therapy could provide a new way to treat the most aggressive breast cancers, bringing us one step closer to beating cancer sooner. 

Jacob

 

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