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Understanding metastasis: Science Groot grant for Erik Danen

A team led by Erik Danen from the Leiden Academic Centre for Drug Research has received a 3 million euros NWO Science Groot grant to unravel the first steps of metastasis. Danen will work together with biologists and theoretical and experimental physicists from Dutch Universities. ‘Understanding these steps could aid future cancer therapy.’

On the move

The most devastating aspect of cancer, and the major cause for mortality, is the ability of cancer cells to ignore tissue boundaries, invade surrounding tissues, and enter the bloodstream. This process, known as metastasis, allows cancer cells to leave the primary tumour and disseminate to other organs. ‘It has long been believed that tumour cells spread across the body by breaking contacts with neighbouring cells and travelling as individuals. However, if you take a good look at tissues of cancer patients, you see something else,’ Danen says. ‘The cells appear to make the journey together, not alone. This is reminiscent of collective cell behaviour observed in wound healing and in embryonal development, where cells travel in groups to repair a wound or move to another place in the embryo.’

Tumour cells moving into their environment

Using a physics theory

This collective behaviour of tumour cells is what Danen and his partners want to understand. ‘We will unravel how a cluster of cancer cells switches from an immobile to a mobile state, how this cluster subsequently passes the physical hurdles in surrounding tissues, and how it penetrates and enters the bloodstream.’ What are the mechanical characteristics of the cancer cells and their environment that control this behaviour? To tackle this question, the team uses a theory from the physics field called active matter. ‘This theory describes the complex behaviour of systems made out of components that consume energy to move or exert mechanical force. Active matter principles can be applied across length scales: from bird flocks down to artificial self-propelled micron-size particles. We are now going to apply them to the biological process of metastasis.’

A flock of birds

The team combines theoretical modelling at different scales with a range of experimental systems. Danen: ‘We have someone in our team who simulates what happens to the whole if you change physical parameters at the level of individual cells. At the same time, Leiden theoretical physicist Luca Giomi will simulate a cluster of tumour cells as one unit. This is much like watching a flock of birds: you can zoom in at the individual birds or view the flock as a whole to describe the dynamics.’ The theoretical insights from computer simulations are tested in various experimental setups in the lab, which, in turn, will generate data to feed into the simulations. ‘This iterative process will continue to describe the collective behaviour of tumour cells with ever-increasing accuracy.’

Tumour cells moving into their environment

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Integrating the disciplines

So how does this process work? Danen’s trick is to let PhD candidates or postdocs work together in different labs, on different sub-questions. ‘Let’s say someone in the Giomi group predicts that if you reduce the force of the interaction between cells by half, clusters of cells suddenly start moving. Using the DNA-editing technique CRISPR-Cas, a PhD candidate in my lab is able to interfere with cell-cell interaction. Someone in the group of Leiden experimental physicist Thomas Schmidt can then accurately measure the interaction force and confirm that it is indeed reduced by half. In my lab, we’re able to quantify the mobility of tumour cell clusters and confirm or disprove the theoretical prediction. After that, the PhD candidate can visit the lab in Eindhoven to study how this same manipulation affects the ability of the cluster of cells to crawl into an artificial blood vessel.

‘Altogether, our project is an example of fundamental science but gaining insight into the process of metastasis is needed to identify means to stop it,’ Danen explains.

Consortium

Partners are from Delft University of Technology, Eindhoven University of Technology, Radboud University Nijmegen and Utrecht University. 
 

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