A snapshot of the pancreas using a new technique developed by researchers at the Francis Crick Institute in London. Credit: Dr Hendrik Messal.

It had been puzzling scientists for decades. Looking at pancreatic tumour samples under the microscope, all they could see were a variety of unexplainable shapes.

A big problem was that the techniques available didn’t capture the whole tumour. Scientists usually study cancer samples by cutting them into very thin slices and taking pictures of the microscopic detail. This can give them a snapshot of the cancer, but it’s hard to build a complete picture.

To help solve this mystery, researchers at the Francis Crick Institute in London developed an entirely new way to look at tumours.

“Nothing like it had existed before and we did see a big need for this,” says Dr Hendrik Messal, who led the project to not just look at cancer piece by piece, but also as an entire organ.

It took the team six years, but eventually they found a way.

A diagram showing the two ways tumour can grow - in our out of the duct.

Tumours can only grow in one of two ways: out of the duct (exophytic) or into the duct (endophytic). Credit: Dr Hendrik Messal.

A FLASH of inspiration

The trick was to make the entire tissue completely transparent while keeping the structure intact. They could then zoom in on particular parts of the tumour by staining them in different colours.

The new technique, which the team called FLASH, allows the researchers to take a closer look at the odd-shaped tumours found in the pancreas of mice. And what they found surprised them.

As part of the digestive system, the pancreas relies on a network of tubes called ducts that transport its digestive secretions to the small intestine. These types of tubes exist in many organs and are common areas for cancer to develop.

And it turns out, despite the dizzying array of shapes that were previously seen under the microscope, these tumours grow in only one of two ways: into the centre of the duct, or out of it. To figure out why these cancers grow in this way, the scientists teamed up with biophysicists to create sophisticated computer models of the tumours.

Geometry not biology

The computer simulations revealed the deciding factor in whether a tumour grows outwards or inwards wasn’t biology, but simple geometry. It all depended on how big the duct was.

When a duct was smaller than 20 micrometres across (about a fiftieth of a millimetre) the cancer would grow outwards. If it was larger, the tumour would grow inwards.

Tumour growing into a pancreatic duct.

Image of a tumour, shown in red, growing into a pancreatic duct. An example of an “endophytic tumour”. Credit: Dr Hendrik Messal.

“As a biologist, you think it’s going to be something to do with the basic biology of the cancer, and of course it plays a role, but the fundamental, important factor that determines how the cancer develops is the tissue geometry,” says Messal.

They found this to be the case not only in pancreatic cancers in mice, but in other organs like the lungs and liver too, giving further support to their theory.

But while the team have begun to figure out what causes tumours to grow in a certain way, there are more questions to answer. The big one being – does it matter which way these tumours grow? They’ve begun to make some progress here too.

The team found that tumours that grow outwards in mice invade the surrounding tissue earlier and can more easily recruit cells that can help the cancer grow and spread to other parts of the body.

What’s next?

For Messal, this work shows the importance of biologists working with experts in other fields – pathologists, physicists, mathematicians, computer scientists – as they can provide valuable insights that biologists just can’t do alone.

The two teams are continuing to work together along with researchers from Imperial College London in a new project looking at breast cancer. They’ll study how the decisions a cancer stem cell makes will affect the how it grows and what shape it becomes.

And as for Messal, he’s now working in the Netherlands Cancer Institute on even more innovative ways to view cancer – not just in 3D, but live. Some processes are dynamic, and these techniques are needed so we can see what’s really happening.

On his experience of this work and his time at the Francis Crick Institute, Messal says: “I’m very much in favour of interdisciplinary science, it was one of the reasons that I wanted to work at an institute like the Crick. The collaboration opportunities these research institutes provide are key to this kind of research.”

Harry Jenkins is a research communications and marketing executive at Cancer Research UK 

Reference

Messal, H et al. (2019) Tissue curvature and apicobasal mechanical tension imbalance instruct cancer morphogenesis. Nature. DOI: 10.1038/s41586-019-0891-2