Studying Cell Mechanics to Understand the Formation of Metastases

Following her initial training in materials science, Claire Valotteau quickly turned her focus to biology: she has just obtained Atip-Avenir funding in order to study the mechanics of circulating tumor cells. This involves the researcher using extremely powerful analysis tools and developing new ones.

Claire Valotteau utilise un microscope à force atomique.
Claire Valotteau is making the adjustments needed to perform an atomic force microscopy observation.

How do embryonic cells move and reorganize themselves to form organs? What are the forces at play when immune cells migrate to their site of activity? And why is a tumor more rigid than its surrounding tissue while individual cancer cells are more flexible? These questions are difficult to resolve through biology alone. This is where biophysics comes in – a science that uses knowledge of fundamental physics to explain the processes of living organisms.

A trained physicist, Valotteau has been working at the interface with biology since her PhD: « During my studies, I specialized in material physics. My dissertation concerned the development of antimicrobial surfaces, which requires an interest in the interactions between the bacteria and materials studied, primarily through microscopic and spectroscopic approaches. » Then, she went on to do two successive post-doctoral fellowships, the first dedicated to the interactions of different bacterial pathogens during the early stages of infection, and the second to the biophysical properties of cancer cells. This enabled her to obtain Atip-Avenir funding in 2021, to conduct a research project on circulating tumor cells: « As a general rule, it is the metastases that are life-threatening in people with cancer. Metastasis forms from cancer cells that leave the initial tumor to migrate to distant organs through the bloodstream. If we were to better understand the mechanical forces and adhesion processes that govern the ability of these cells to detach, pass through the vessel wall and implant into other tissues, it would be easier to envisage combating the formation of these metastases, » explains the researcher. The existing data show that a cluster of circulating tumor cells has a greater probability of producing metastasis than the same number of cells circulating individually. « We therefore want to characterize the properties of isolated cells and cell clusters, and better understand the incredible ability of these cell aggregates to change shape in order to pass through thin capillaries and penetrate tissue. »

From atomic to acoustic force

In order to describe the elasticity and adhesion dynamics of these cells, the researcher uses atomic force microscopy (AFM). As its name suggests, this imaging technique is used to describe elements on the atomic scale. « The principle of AFM is not based on the use of light but on that of an infinitely small tip that is 10,000 times smaller than a hair! It is placed in contact with the element studied and can be moved using an extremely sensitive lever. The tip’s movements on the surface are detected by a laser. It is like the diamond tip of a record player stylus or a blind person’s cane in miniature, except that here the aim is not to find our way down a street but rather to reproduce the topography (3D image) of a cell! Furthermore, the elasticity of the sample can be evaluated using the force applied by the lever. Finally, by gradually raising the tip, we can measure the adhesion forces. »

Thanks to her Atip-Avenir funding, the researcher was able to recruit a student who will start his PhD in the autumn, and who will soon be joined by an engineer. Their objective will be to develop acoustic force spectroscopy, a novel analytical technique that uses sound waves to manipulate objects on the micrometric scale. « We are looking to develop this new technique to study mechanical properties at cell level. Its data would complement those of AFM. » Indeed, while the latter requires fixing the cells to the surface, acoustic force spectroscopy would offer the means of studying cells in suspension, and therefore more closely qualify the behavior of isolated and aggregated circulating tumor cells.

« Our research focuses on the biophysical properties of the cells we are studying, but we regularly interact with biologists, explains the researcher. Our work, although conducted with perspectives related to the physical sciences, will help biologists to understand metastatic phenomena in greater depth, in order to open up new therapeutic avenues. » It is evident, then, from this approach that interdisciplinarity is crucial to medical advances and the furthering of knowledge.

Claire Valotteau is leader of the Biophysics of circulating tumor cells, from single molecule to cell cluster team in the Adhesion & Inflammation lab (unit 1067 Inserm/CNRS/Aix-Marseille Université), in Marseille.