Combining models and molecules to understand metastasis

Cancer Research UK
Library picture, CRUK LRI Cell Motility Laboratory

 

Using funding from the CRUK–EPSRC Multidisciplinary Project Award, Mathematician Dr John MacKenzie from the University of Strathclyde and molecular biologist Professor Robert Insall from the CRUK Beatson Institute have teamed up their respective skills to take a novel approach to understanding cell migration.

The combined power of computer theory and cell biology

Understanding the transformative influence that new skills and techniques can bring to research, Robert and John have brought together a group of mathematicians, statisticians and cell biologists to tackle one of the most fundamental challenges in cancer research – metastasis.

In isolation, classical mathematical approaches – excellent at uncovering linear pathways – struggle to explain the complexity of positive feedback and self-organisation involved in cell migration. To overcome this, the team are using a combination of theoretical and experimental components.

They are first designing new realistic computational models to describe how individual molecules drive the shape, movement and steering of a cell when it is driven out of a primary tumour and into the blood, lymph and surrounding tissues – a process which is responsible for around 9 in 10 deaths in people with solid tumours. The theoretical results are then tested experimentally by tracking melanoma cells using video microscopy, with the team adapting their predictions for comparison to data derived from real tumours.

Taking time to build the right team

The pairing of skills between these teams is enabling real innovation in how researchers can think about cell migration, but John explained that the collaboration didn’t happen overnight:

Robert contacted the mathematics department at Strathclyde back in 2008 looking for possible collaborators willing to get involved with the computational modelling of cell migration and chemotaxis (the process of cells moving across self-generated gradients of molecular signals, which are created when cells take up or break down the molecules around them). He was particularly interested in models that could explain the experimentally observed phenomena of pseudopod splitting and its role in chemo-taxis.
Although I had no previous experience of mathematical modelling in biology, I was fascinated by Robert's movies of cell chemotaxis. As a team we worked well and made rapid progress with an initial model that captured many aspects of real cell behaviour in a relatively simple system.

As well as progressing their understanding of metastasis, which can hopefully lead to improving treatments and survival rates, both researchers will be armed with new insight they can carry with them to other areas of their research.

Simulating cell movement, Image courtesy of John MacKenzie

This simulation demonstrates how mathematical modelling can uncover unexpected traits of cancer cell movement. Here, the cell is initially surrounded by equal amounts of ligand (the chemical it is attracted to). The simulation plots the cell’s response to changing concentrations, caused by slight imbalances in the rate at which the cell breaks down the ligand - blue indicates low levels around the cell and red indicates high levels. As the cell breaks down the ligand it changes shape and distribution of surface receptors which interact with the chemical, resulting in distinct patterns of movement.

A clear clinical direction

The results of this multidisciplinary study will help researchers to further understand the range and capabilities of self-organisation. This will encourage future research into the causes of metastasis, allowing clinicians to better identify what causes tumour cells to spread in vivo and leading to more accurate diagnosis and the development of metastatic treatments. This simulation demonstrates how mathematical modelling can uncover unexpected traits of cancer cell movement. Here, the cell is initially surrounded by equal amounts of ligand (the chemical it is attracted to). The simulation plots the cell’s response to changing concentrations, caused by slight imbalances in the rate at which the cell breaks down the ligand - blue indicates low levels around the cell and red indicates high levels. As the cell breaks down the ligand it changes shape and distribution of surface receptors which interact with the chemical, resulting in distinct patterns of movement.

The committee’s verdict: complementary and realistic experiments

The committee who reviewed Robert and John’s application agreed that the team’s proposal outlined a clear set of complementary and realistic experiments. They praised the high quality of the mathematical models John had designed, and felt Robert's previous work and expertise in different approaches to experiment design provided a strong indication that, together, the team could achieve what they proposed.

The Multidisciplinary Project Award is co-funded by the Engineering and Physical Sciences Research Council (EPSRC) . The next deadline for the scheme is 25 January 2017, please get in touch if you’d like to discuss a project idea.