How it works: using human tissue to model human bowel cancer

Tissue stiffness

We study how the physical properties of tissue - like stiffness - are critical for bowel cancer to progress. Bowel cancer, like many cancers, often has very dysregulated tissue structure. It becomes stiff, fibrous and dense.

The image here shows what this looks like in a patient with bowel cancer. Surrounding the tumour are fibres which are denser than normal tissue fibres, imaged using a specialised microscope that emphasises these thicker fibres with brighter signal (Delaine-Smith et al, 2019).

Animal-free bowel cancer research

Our team uses models in the lab, growing "mini tumours" in a way that enables us to study these tissue changes. We use what we call "organotypic" tissue mimics using normal cells alongside cancer cells in a 3D gel to mimic the fibre structure. Crucially, we don't believe this process is captured accurately in the animal models frequently used in cancer research. This may contribute to why so many potential anti-cancer drugs fail in people despite being successful in mice.

The role of enzymes

In 2019, our team looked at the role of an enzyme called transglutaminase-2 (TG2). TG2 functions like a glue - binding tissue fibres together, similar to when a wound heals.

You can see TG2 stained green in these images, showing a patient sample and our gel models. Cells in the images are stained blue. This work was funded by Bowel Research UK

The tissue stiffness paradox

However, these early studies appear to show a paradox.

The presence of TG2 seemed to slow down how quickly cancer cells invade and spread. This would normally be viewed as positive to patient outcome.

However, when we measured the enzyme in patients, it seems that having less is actually associated with better survival rates. High levels are much more deadly.

Our team currently focusses on this "double edged sword".

TG2 is a barrier to treatment

In 2023, Filipe Hanson worked on an MRC-funded project showing that blocking TG2 allowed chemotherapy agents to better access cancer cells in our models.
This was our first evidence that TG2 forms a "barrier" to successful treatment, and a potential explanation - cancer cells survive drug treatments and are ready to re-start growth once treatment has finished.

"Unmasking" hidden cancer cells

Alexandra Fiala is a PhD student funded by Bowel Research UK. She uses mini-tumours (tumoroids) to study whether this barrier enables certain cancer cells to hide until after treatment has finished.
This may explain why recurrence happens - bowel cancer returns in around 30% of patients even when treatment seems to have been successful.
This image shows what happens when we block TG2 - we deliver drug more effectively (red) and kill more of the tumoroids.

Humane research - using human tissue to model human disease

Our research is critically dependent on building realistic tissue models of bowel cancer progression.
Previous projects funded by Animal Free Research UK have enabled us to show that we can build models substituting commonly used lab components that are sourced from animals, showing that we replace these with more humane alternatives.
Gels made from animal collagen are a common lab component for making 3D cancer models - but thanks to Transition Grant funding we began to develop human tissue gels to model human cancer - taking surgical waste and turning it into material to build our more human-like cancer models.
We have recently been awarded generous funding by The Humane Research Trust to continue this progress in a completely animal-free, animal product-free way - building advanced systems that model human tissue structure, bowel cancer, and immune responses that are seen in the human body. More to follow very soon!
We'll use these models to continue asking whether targeting TG2 and the tissue structure can lead to better treatment by enabling drugs and the immune system to better access and see the cancer cells within this dysfunctional, fibrous tissue environment.

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