Memories are like records of our past experiences. Stored in our heads, they keep the lessons we’ve learned readily to hand and shape how we approach the future.

Strange as it might sound, our cells have memories too. They record them as chemical marks on their DNA. And just like us, their memories influence how they behave and respond to future challenges.

That’s usually a good thing, but we’ve all had times when our memories of one situation become unhelpful in another. Sometimes, holding too tightly to the past can cause its own problems.

Cancer Grand Challenges team PROSPECT has found evidence that cells can fall into the same trap. The team’s latest animal study suggests that the way some bowel cells remember the body’s natural healing process (inflammation) could be priming them to turn into tumours.

Normally, inflammation helps the body recover from injuries and infections. Although it plays an important role in keeping us healthy, scientists have observed that when it goes on for too long, it can also increase people’s risk of bowel cancer.

Now, PROSPECT’s findings are helping show why this happens. In particular, they’re filling in an important piece of the puzzle in explaining why people with inflammatory bowel conditions like ulcerative colitis (chronic inflammatory bowel disease) have a higher risk of bowel cancer. Although the team have only looked at mouse models so far, their work could one day help prevent bowel cancer in humans.

How cells ‘remember’ their past

Focusing on our cells’ memories is a new way to think about cancer risk. To understand it, we need to take a closer look at our cells’ DNA.

Most images of our DNA show it as a long, twisted ladder. But inside our cells, it looks more like tightly wound balls of yarn. Thousands of proteins coil our DNA into bundles so it can squeeze into the tiny space in the centre of our cells.

And these bundles do more than just organise our DNA. They also work like genetic gatekeepers. Chemical marks can tell them to unravel or wind up DNA to turn specific genes, or instructions, on or off. This helps our body create many kinds of cells, with different forms and functions, from identical strands of DNA.

These marks are known as epigenetic modifications. Though we inherit some from our parents, most are acquired throughout our lifetime from many different factors. Often, they can help cells remember what they’ve been through and adapt their behaviour.

Uncovering the ‘marks’ of inflammation

To create a mouse model for their study, the researchers used a chemical to mirror the effects of chronic colitis. Afterwards, they looked for changes in the mice’s bowel cells.

Through the microscope, the bowel cells looked normal; but their DNA told another story. It had picked up a distinct set of chemical marks, some of which had gathered around genes targeted by a protein called Activator Protein 1 (AP-1).

AP-1 is a special type of protein known as a transcription factor. Its job is to control when cells read and use genes involved in healing and regeneration.

With each round of inflammation, the cells added more marks to their DNA, making it easier for AP-1 to access these genes. That way, the next time inflammation returned, the cells could turn them on more readily to heal faster.

What really surprised researchers was how long these marks lasted. Most bowel cells are replaced frequently, so these memories should have disappeared soon after the inflammation ended. But after 100 days, the researchers were still finding cells with these marks.

When they investigated further, they found that inflammation had even affected the DNA of cells in the deepest layer of the bowel: colonic stem cells. These long-lived cells continuously create new cells to help maintain the lining of the bowel. They were copying their epigenetic marks into each new cell they produced, keeping the memory of inflammation alive.

Linking ‘memories’ and cancer

Once the researchers figured out how the memory of inflammation was being maintained in the bowel, they wanted to see if it might influence the development of bowel cancer.

They mutated the DNA of the mice’s bowel cells to encourage them to become tumours. Then, when they looked in the mice’s intestines, they saw something dramatic: mice that had chronic colitis developed larger tumours than those that didn’t.

After analysing the tumours, the researchers found that the larger ones were made up of cells with memories of chronic inflammation. The cancer-causing mutation led these cells to use the same genes that helped them heal during inflammation to grow uncontrollably.

“We’re finding that a cell’s memories, the experiences it’s had in the past, are quite influential in whether or not it’ll make the leap to cancer,” says Dr Jason Buenrostro, the Harvard University professor who supervised the research. For him, the study raises the possibility that the things a cell remembers – its epigenetic changes – could be “the missing piece” for understanding how long-term inflammation can lead to bowel cancer.

A new approach to preventing cancer

Equipped with their new understanding, the researchers now plan to see what memories are recorded in bowel cells of people with early onset bowel cancer. They hope to identify marks that may be influencing how bowel cells develop into tumours.

“This research could help us understand who is most at risk and inform new approaches to help prevent or intercept bowel cancer at an earlier stage,” says David Scott, Director of Cancer Grand Challenges. “It’s a powerful example of the kinds of breakthroughs Cancer Grand Challenges was designed to achieve.”

PROSPECT also plan to expand their studies to look at whether alcohol and diet may epigenetically influence bowel cancer risk.

“We all walk around with cancer-related mutations, but we don’t all have cancer,” says Buenrostro. “It’s not just the genetic mutation that matters – the cell type and the experiences that cell has will determine disease outcomes.”

This is the good side of looking back. By uncovering how bowel cells remember the past, and identifying when those memories lead them astray, PROSPECT is helping us find new ways to prevent bowel cancer in the future.

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