The mysterious stem cells that could hold the key to beating bowel cancer

At first, her GP thought it was appendicitis.  

One evening in August 2023, Sharon experienced a sudden stomach pain that, she says, “was nothing I’ve ever had in my life. I was doubled over, I just couldn’t move, and I stayed like that all evening.” 

Her GP sent her straight to A&E, where blood tests ruled out appendicitis and she was booked in for a colonoscopy. 

During the procedure two weeks later, the doctor looked at the screen and told Sharon words she’ll never forget.  

“He said, ‘Oh, that’s got to come out. You’ve got a tumour.’”

By June 2024 she was told she was clear of cancer. But six months later, this January, a routine colonoscopy found another small tumour in her bowel, which a follow-up scan had missed.  

Sharon’s now recovering from an operation at UCL Hospital to remove the secondary growth. And as she does, cells from that tumour are helping researchers solve an enduring mystery: why do some cancers come back, even after surgery and intensive chemotherapy?

It’s a fundamental question. And at the UCL Cancer Institute in London, Cancer Research UK’s Professor Chris Tape is closing in on answers. Helping him, in his lab, are Sharon’s tumour cells, growing in microscopic 3D structures called organoids. 

Communication breakdown 

Chris’s lab at UCL studies how cancer cells interact with their surroundings – collectively referred to as a tumour’s microenvironment.  

“Normal cells are essentially controlled by two things: their genes and signals from their environment”, says Chris. “In cancer, a growing tumour is a unique mixture of cancer cells – which have damaged genes – and healthy cells, and my lab is interested in understanding how all these cells communicate to drive bowel cancer.”  

One way cells communicate is by releasing chemical signals which are absorbed by their neighbours, which then, in turn, triggers a cascade of internal molecular changes causing them to change behaviour. But studying these signalling networks can be fiendishly tricky.

Bowels in a dish 

The solution to the first problem arrived in the early 2010s, when researchers in the Netherlands developed a completely new way to study living systems: organoids.  

“Organoids are microscopic, three-dimensional models for studying how cells self-organise into tissues,” says Chris. They’re created from specialised cells called stem cells. When these cells divide, one of the resulting ‘daughter’ cells remains a stem cell, but the other can change into different kinds of cells in the body. In doing so, stem cells help the body grow, and repair damaged tissues. And research has shown that rogue stem cells are particularly important in cancer, fuelling a tumour’s growth by endlessly churning out new cancer cells.  

The Netherlands researchers had isolated stem cells from gut tissue and found a way to encourage them to form microscopic gut-like structures, made of just a few thousand cells, that recreated many of the cellular structures found in a healthy bowel. Crucially, they also showed how stem cells from patients’ bowel tumours could be grown into miniature bowel cancers. 

When he first heard about organoids, Chris was intrigued by their potential for studying cell communication in cancer. “Organoids are much cheaper and easier to work with than animal models like mice. Working out how to study them at scale would be a powerful way to run thousands of experiments on cells from dozens of patient’s tumours,” he says. 

At around the same time, tragically, Chris’ mentor – world-renowned cancer researcher Professor Chris Marshall – developed incurable bowel cancer himself. “My grandmother died of bowel cancer when I was a teenager, so seeing a scientific legend like Chris experience a similar fate really brought bowel cancer to the forefront for me” says Chris. “At the time no one really understood the tumour microenvironment in bowel cancer, but it was clear that it was very important, and I couldn’t stop thinking about it.”  

Alongside organoids, another technological revolution was emerging, allowing scientists to study individual cancer cells one at a time. “It’s been an absolute game-changer for cancer research,” says Chris. “Tumours are ecosystems of millions of interacting cells and now we have the technologies to see what every cell is doing.” 

Central to Chris’ work is a powerful machine known as a CyTOF, which allows organoids to be broken down and analysed one cell at a time. This means researchers can grow multiple different samples of identical organoids under different conditions, then use the CyTOF to measure how each condition changes how organoids behave, including changes in multiple different signalling molecules inside their cells. Crucially, it allows them to do this at a scale and speed that would be impossible using animal models. 

This scale becomes even more powerful when applied to organoids grown from different patients’ tumours. And because no two patients have identical tumours, this has allowed Chris’s team to start to decipher the underlying rules that govern how bowel cancers respond to treatment.

A stem cell revival 

Through crunching data from millions of cells from thousands of experiments on different patient organoids, Chris’s team have started to reveal why some cancers are able to return after treatments like chemo- and radiotherapy. And key to this has been the breakthrough discovery of an entirely new type of stem cell inside bowel tumours.  

“Normally, bowel cancer stem cells are so-called ‘proliferative’ stem cells. These are similar to healthy gut stem cells, but ‘turned up to eleven’ by the DNA mutations they carry,” Chris says. “They’re what you classically think of as cancer cells.

“But we’ve discovered that bowel cancer cells aren’t always like this. In fact, they can change very quickly into so-called ‘revival’ stem cells – normally, this is a survival state that the bowel enters following damage or infection. It seems that bowel cancer cells can ‘remember’ how to access this state and use it to their advantage,” says Chris. 

Crucially, these revival cells are stubbornly resistant to chemotherapy or radiotherapy. “It’s relatively easy to kill fast-growing cancer cells – it’s how chemo and radiotherapy work” says Chris. “But revival stem cells slow down their growth, so treatments don’t work on them.” 

Chris’ team have shown that different patients’ stem cells seem to differ in how easily they flip into a revival state – providing an explanation for why some patients’ cancers come back after treatment. Crucially, they’ve also discovered that signals from other cells in the tumour microenvironment, called fibroblasts, are responsible for flipping fast-growing cancer cells into the revival state.  

Ultimately, Chris thinks finding a way to specifically target revival stem cells could revolutionise how bowel cancer is treated, preventing the disease from returning after therapy and, potentially, curing it.  

“My lab is basically at war with these cells now,” he says, and they’re now working on strategies to block, target, and kill them.  

TAILORing treatment to beat cancer 

Since these discoveries, Chris has been awarded £1.5m funding from Cancer Research UK to find out more about the communication networks that trigger the revival stem cell state, through a programme called TAILOR. 

“We want to uncover the fundamental rules behind why different patients respond differently – and that means analysing organoids from lots of patients,” says Chris. As part of this project, his colleague Petra Vlckova from Cancer Research UK City of London Centre’s Organoid Platform will collect samples from 50 people who’ve had surgery for bowel cancer at UCL Hospital. This includes taking samples of their stem cells, to create cancer organoids, but also neighbouring fibroblasts to help decipher the cellular cross-talk, and healthy tissue and blood to build a complete picture of each patient’s disease. “The Organoid Platform acts as a bridge to connect patients in the NHS with cutting edge laboratory science” says Petra. “Programmes like TAILOR will fundamentally change our understanding of bowel cancer.”