Cancer metabolism: finding how fast-growing cancers get their energy

Cancer is notoriously complex, but it’s underpinned by the simple fact that cells need energy to grow. While taking on their Cancer Grand Challenge, team Rosetta found how some of the most aggressive and hard-to-treat breast cancers get the fuel to grow and spread so quickly. Now we can see about slowing these cancers down.

Life relies on metabolism. As different as an oak tree is from an octopus, or Brad Pitt from a bacterium, they all exist because their cells (or their cell) can turn food into energy, as well as other important building blocks. It’s the same with cancer cells, which metabolise nutrients in ways that help them grow and spread, and cancer researchers, who pour their energy into finding new ways of stopping the disease.

“Metabolism is everywhere,” explains Dr Mariia Yuneva, senior group leader at the Francis Crick Institute and co-investigator in Cancer Grand Challenges team Rosetta, who recently concluded their work on the 3D tumour mapping challenge. “It’s one of the bases of life.”

We tend to think of bases as solid, independent things, but metabolism isn’t stable. It changes, just like we do. When did you last eat? If it was recently, your cells will be turning that food directly into energy as you read. If you can’t focus for the sound of your stomach rumbling, you’re probably breaking down stored nutrients to keep yourself going.

Get a snack if you need one: we’re zooming in. Close up, we can see that cells in different parts of our bodies get and use their fuel in different ways. When we exercise, the ones in our muscles activate special mechanisms to give us energy more quickly – but that might involve different nutrients in our heart than it does in our arms and legs.

For all those little differences, multiple types of cells can still work together to focus energy on healing when we’re injured or ill. Keep zooming and panning and you’ll begin to see that we’re a metabolic system, with every subtly different part interlocking to support the whole.

This would be a nice place to stop, but we’re looking for something else. Rosetta’s work started because of the ways that system can break down.

Cancer and metabolism

Here’s a cell that doesn’t seem to fit. It’s sucking in more nutrients than it should need. Now it’s two cells. Now it’s four. It’s eight cells pushing others out of the way. It’s 16 cells in metabolic overdrive.

This is cancer.

Over time, mutations and copying mistakes built up until that first cell began to divide without respect for its place in the body. It started acting as if it was the whole system, rather than a part of a bigger one. That’s our most basic definition of cancer: “when abnormal cells divide in an uncontrolled way”.

We usually think about cancer in terms of changes to genes, which give individual cells their specific instructions, effectively controlling how they act. But cancers don’t just grow because genetic changes mean cells lose control. They also need to gain energy. A mutated cell that doesn’t have the energy to multiply is much less of a problem, so metabolic changes are a big part of what makes cancers dangerous.

It’s a bit like why we have speed limits. The faster you drive, the more fuel you use, and the bigger the risks you take. A car that crashes at 70 miles an hour ends up looking very different from one that crashes at 30.

Using some of the funding they received from Cancer Grand Challenges, which we co-founded with the National Cancer Institute in the US, Rosetta found a way to see how cancer cells get the energy they need to break speed limits. Their work could give us a way to slow them down for good.

A grand challenge and a big discovery

All the zooming and panning we’ve done to get here is thanks to Rosetta, too. The £16m Cancer Grand Challenges gave them to take on the 3D tumour mapping challenge meant they could develop an entire tumour-tracking imaging system. From the start, it was designed to be cancer research’s equivalent of Google Earth. But Google Earth’s satellite cameras just show what the planet looks like, not how it uses energy. Rosetta’s mass spectrometry imaging tools can zoom in to show how the metabolism of every single cell of a living tumour changes over time. 

Nothing like this has ever been available to cancer researchers before.

“Lots of people have been thinking about how we can get cells out of tumours and measure their metabolic activities,” explains Yuneva. “But it’s virtually impossible, because metabolism is so fragile, and it’s very mobile and flexible. You have to do it without disturbing the cells. That’s why this imaging is so useful and exciting.”

How useful? Well, to find out just what Rosetta’s imaging tools can reveal, Yuneva’s team pointed it at breast cancers containing cells with mutations affecting a gene called MYC. Those are some of the most consequential mutations of all. Highly active MYC genes are associated with more aggressive, harder-to-treat cancers, and worse outcomes for patients.

The more active MYC gets, the faster cancer cells divide. And high MYC activity can also set cancer cells on the path to metastasising: breaking off and spreading to form a new tumour somewhere else in the body. Most people who die from solid cancers have metastatic disease. If we can work out how to deal with MYC, we can save lives.

We’ve known that for over 40 years. The problem is we still don’t have any drugs that can specifically target MYC. Now, though, Rosetta’s metabolic cameras have revealed some weak points. It turns out that many of the advantages MYC mutations bring to cancer cells are dependent on one key way of getting energy.

Restrict that energy source, and we might be able to take those cancer-driving advantages away.

“All of it stopped”

It was Dr Peter Kreuzaler, a former member of Yuneva’s group at the Francis Crick Institute – and now the head of his own research team at the University of Cologne – who made that connection.

He joined Rosetta after creating a way of comparing breast cancer cells with high and low levels of MYC activity in a single tumour. Combining it with Rosetta’s imaging systems has allowed him to consider more differences than ever before.

Given what we know about MYC, it wasn’t a surprise that the fastest growing cells in Kreuzaler’s models – both in mouse tumours and human tumours transplanted to mice – had the highest levels of MYC activity. Unexpectedly, though, Rosetta’s metabolic satellite also showed that they had very high levels of a nutrient called pantothenic acid, or vitamin B5.

Images showing that the areas of a breast cancer tumour with high Myc activity also have the most pantothenic acid. — These images of breast cancers in mice show the correlation between cells with high Myc activity (green cells on the left) and areas with more pantothenic acid (lighter colours on the right). Photo by Peter Kreuzaler.

That kind of correlation can show up randomly, but Kreuzaler was new enough to studying metabolism to think it was worth taking a closer look.

“I had no preconception of what should be interesting,” he explains. “Had I been more primed to look at the ‘usual suspects’, I think I would have filtered this out.”

When the team reduced the levels of vitamin B5 in the diets of their mouse models, it became clear they’d spotted something important. Without vitamin B5, breast cancer cells driven by MYC mutations slowed down until they were growing and dividing at the same relatively slow speed as the other cancer cells in the tumour.

“Everything that cancer cells gain by upregulating this oncogene MYC – which we know almost always happens when tumours are progressing from non-invasive to invasive – all of it stopped when we took away a single vitamin,” says Kreuzaler.

“Immediately, we could see that these tumours were struggling. The cells that, up until that point, were driving growth the most couldn’t do so anymore.”

A new frontier in cancer research

This is the first time scientists have been able to investigate how different mutations shape the metabolism of different areas of a tumour. That’s important because cancers keep mutating over time, so multiple cells in the same tumour – far too close for our eyes to tell apart – can have very different mutations and ways of making energy.

Those differences can have a big impact on how cancers grow. But they’re only the tip of the tumour iceberg. As many as half of the cells in what’s called the tumour microenvironment might not be cancer cells at all. They all play a role in how cancers develop, and we might even be able to manipulate some of them to take cancers apart from the inside.

No power without fuel

“What staggered me is that I knew MYC upregulates [turns up] easily a third of the entire genome,” Kreuzaler says. “We took away one single compound, and 12,000 genes just didn’t seem able to do what they wanted to do anymore.”

No one on Rosetta had realised quite what their tools were going to show them. They’d found the connection that gives MYC its real power.

Cells use vitamin B5 to create a molecule called coenzyme A, which supports almost all of their energy creating processes. The only way for Vitamin B5 to get into cells is through a molecule called the sodium-dependent multivitamin transporter. That’s made by a gene called SLC5A6.

Working backwards, the team showed that MYC is responsible for upregulating SLC5A6. Normally, that relationship makes sure cells get energy boosts when they need them. For cancer cells to grow and spread aggressively, though, MYC has to convince SLC5A6 to stay on all the time.

A sample of a human tumour seen through team Rosetta's tools. — The brighter areas of the top image show higher concentrations of pantothenic acid in a human tumour sample. They correspond with the darker parts of the lower image, which show the areas with higher Myc activity. Photo by Peter Kreuzaler.

If it couldn’t do that, MYC wouldn’t seem so important. When Rosetta created more multivitamin transporters in cancer cells without MYC mutations, those cells grew faster, too. It’s the availability of the energy that makes the difference.

And, despite the many mutations that tend to follow MYC, Rosetta didn’t see any evidence that cancers driven by it can find new ways to make energy when vitamin B5 is scarce.

“We were entirely sure the cells would start relying on another pathway to create energy, but they didn’t,” says Kreuzaler. “Everything was being processed the same way, just a lot slower.”

At that speed, cancer cells are much less likely to outrun our treatments.

Turning a finding into a treatment

This is lab research in mouse models of breast cancer, so we’re still a long way from applying it to humans. But it shows the incredible potential of using Rosetta’s platform (which is available to scientists around the world) to investigate cancer metabolism.

Two electron microscope images showing that tumour cells with high Myc activity have higher levels of glucose and glutamate, which are both important for metabolism. — Cells with high Myc activity and more pantothenic acid can make more use of glutamine (concentrated in bright areas on the left) and glucose (right) to create energy. Photo by Peter Kreuzaler.

“For a long time, cancer research was all about genetics and signalling, not metabolism,” says Yuneva. “It didn’t occur to people that molecules like pantothenic acid are at the base of everything that they study.”

They’re at the base of a lot more. Vitamin B5 is important to how lots of our cells create energy. And it’s almost impossible to avoid. The name ‘Pantothenic acid’ comes from Ancient Greek. It means the acid on all sides. We even have microbes in our gut that produce it.

In short, this research is not going to lead to a future where we change our diets to cut out vitamin B5. Meals would be sad without it; and, like all vitamins, it helps keep us healthy. Most of the time, avoiding it would make us more likely to get ill. But scientists can now start thinking about developing and testing targeted ways to lower levels of vitamin B5 during cancer treatment.

Cancer metabolism and the immune system

That’s a very delicate balance.

Rosetta’s mouse models didn’t have functioning immune systems, but every human tumour has cancer-fighting cells in it, too. They’re our first line of defence against the disease. Rosetta’s satellites give scientists the chance to watch them in action.

Immune cells almost always eradicate potential cancers. The cancers doctors diagnose and treat only start on the rare occasions that abnormal cells grow and divide fast enough to establish a tumour before immune cells can stop them.

Even then, things enter a sort of stalemate. It takes a lot of energy, but the immune system can keep a cancer from spreading or causing harm for months or even years – until a mutation tips the scale.

Of course, this is the process we’ve been talking about all along.

We know MYC mutations are associated with cancer cells breaking off from a tumour and spreading through the body. We also know that that can’t happen until these cells find a way to suppress, trick or escape the immune system. What if pantothenic acid is key to both?

“The immune system relies on what we call a high-energy biosynthetic metabolism as well,” explains Kreuzaler. “So, there could be a competition there for energy.”

If MYC-driven cancer cells suck up all the available vitamin B5, then immune cells might not be able to keep making the energy they need to keep them in check. It’s almost the perfect crime: not even the police’s best drivers can chase the criminal who stole all their fuel.

The energy to keep going

To fully understand how we can manipulate cancer metabolism to help treat MYC-driven cancers, researchers will need to study the role pantothenic acid plays in the full tumour microenvironment. Thanks to Rosetta, they’ve got the just the tool to do that. And, even though the team’s Cancer Grand Challenges funding period is over, Kreuzaler isn’t finished zooming in just yet.

“We don’t want to disproportionately disadvantage the immune system,” he says, “so we’re going to look at how breast cancers and T cells interact when there are different levels of pantothenic acid. And then we’re going to manipulate the T cells in a way that they hopefully become more proficient at utilising vitamin B5 as well.”

“As we keep developing our technology, we’ll be able to unpick, cell by cell, how we can hit the tumour and not the immune cells.”

That’s the level of detail and attention progress takes. Rosetta have made it possible to study metabolism in greater detail than ever before. Fittingly, they were supported by something very similar. Cancer Grand Challenges is an interlocking system that makes sure the world’s best researchers can work together and focus their energy on the most important questions. Cell by cell, donation by donation, and moment by moment, it’s taking us further.

Tim

Kreuzaler, P., Inglese, P., Ghanate, A. et al. Vitamin B₅ supports MYC oncogenic metabolism and tumor progression in breast cancer. Nat Metab 5, 1870–1886 (2023).