"One of the commonalities between division and migration is that they both involve shape change," Guillaume Charras of University College London tells medicalphysicsweb. "And by understanding the mechanisms that give rise to this, including the signalling – which underpins key stages that the cells must go through to divide or to migrate – we may be able to identify related proteins as targets for drug treatment."

Joining Charras in leading the Cancer Research UK/EPSRC-funded project is Guillaume Salbreux, who is based at the Francis Crick Institute in London. Charras and Salbreux are pooling their experimental and theoretical skills to attack the problem on multiple fronts.

"The stipulation that the project team should have one investigator with an experimental background and another bringing a theoretical perspective is something that was very important to us in making the decision to apply for the [Cancer Research UK/EPSRC] grant," Charras explained.

The scheme is designed to fund teams linking biological researchers with physical scientists and engineers to work on challenges in cancer.

In the lab, Charras provides experimental expertise on the cell cortex, while Salbreux's theoretical interest includes the cytoskeleton. The combination puts the team in a strong position as their multi-year project gets underway.

Investigating mechanical properties

The cell's submembranous actin cortex – a thin meshwork of actin filaments, myosin motors and actin-binding proteins – is a major determinant of cell stiffness and cell shape. And the researchers are beginning their study by examining how signalling changes the mechanical properties of the cortex, as well as how these changes in mechanical properties then lead to shape change.

To evaluate the mechanical properties of the cell, the scientists probe their samples with an atomic force microscope, which indents the surface with a microfabricated tip. "[Another option] is to squash the whole cell underneath the flat part of the cantilever, which provides a readout of the surface tension," Charras adds.

The experimental sequence begins with an optical signal applied to the cell membrane, which initiates the shape change by targeting signalling proteins coupled to the surface. It's a technique borrowed from the field of optogenetics, which exploits conformational changes in proteins that are induced by exposure to light.

To direct the beam, the scientists use a confocal microscope. "We also use the instrument to acquire stacks of images that allow us to reconstruct the profile of the cell in three dimensions," Charras points out.

These data are important as they allow Salbreux to compare his theoretical predictions, which are also rendered in 3D, with the experimental results from Charras' lab. "The physical modelling allows us to determine if the mechanical responses that we detected are sufficient to explain all of the shape changes in the cells, or whether we need to look for something else that we have missed," he comments.

To describe the skin of the cell, Salbreux considers the cytoskeleton – which contains multiple filaments and motors – as "blocks" of active fluid. "It's active in the sense that it uses energy provided by the cell, and is driven out of equilibrium by internal processes occurring inside the fluid," he clarifies.

Using a theoretical toolkit that includes computational fluid dynamics, the scientists are attempting to predict how the cell shape is going to change and how fast it is going to change once the signalling perturbation has been applied. But it's not just about matching the simulations with the experiment – the modelling process also needs to be efficient. "One of our major targets is to find the fastest and the most elegant way of doing this," Salbreux adds.

The group's results should provide valuable insight into how cells and tissues change their shape in a controlled way. "In the lab, we're looking at the mechanics of two-dimensional sheets – or monolayers – of cells, which represent very simple tissue structures," said Charras. "And using exactly the same tools, we're hoping to control the mechanics of a few cells within that layer – to see if we can make it bend out of plane, or if we can contract the tissue in one direction and elongate it in the other." The longer term goal here is to try and replicate morphogenetic changes observed in larger-scale growth.

• This article is the third in a series looking at some of the research funded through the CRUK–EPSRC Multidisciplinary Project Award. In addition to this scheme, Cancer Research UK offers a range of funding opportunities open to researchers not currently working in cancer who are seeking to focus their expertise to this area: Pioneer Award; Early Detection Programme and Project Awards; and Grand Challenge.

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