Biomechanical analysis of collective cell migration in vivo

Cell migration is essential for wound healing and immune response, and it is activated during invasion of cancer cells. All these migratory cells exhibit the same behaviours as embryonic cells. For example, during embryonic development cells move throughout the body, a phenomenon echoed in the movements of cancer cells during metastasis. This has led researchers to suppose that the molecular mechanisms driving these processes may be similar. Therefore, we will study cell migration by using the neural crest cells, an embryonic cell population whose migratory behaviour is similar to the invasion of cancer cells.

Cell migration can be compared with a person walking: both need to sense the signs that indicate the direction of movement as well as the mechanical properties of the substrate used for locomotion. It is not the same to walk on the pavement than to walk on sand. While the role of molecular signals in cell migration is comparatively well understood, how tissue mechanics influences migration in vivo remains unknown. Neural crest is the ideal system to study cell migration as it is amenable for in vivo studies, as well as for molecular and mechanical manipulations of the substrate used for locomotion. In addition neural crests migrate as clusters of cells, an intensely studied but poorly understood process called collective cell migration. We will measure the hardness of the substrate that is required for neural crest migration in vivo, and test the requirement of these mechanical properties to control the initiation of cell migration as well as its directionality. In addition we will analyse how cells sense the mechanical properties of the substrate. As far as we know, this will constitute the first study investigating the role of mechanical cues on collective cell migration performed in vivo, and it will have wide implications in understanding cell migration in many physiological situations.

Cell migration is essential for development, adult homeostasis and cancer invasion. Although research on cell migration has seen considerable progress in recent years, most of it has focused on the molecular signals that control single cell migration in vitro. This is in spite of the growing realisation that many cells migrate in vivo not as single cells, but as clusters, a process called collective cell migration. A second aspect that has been largely ignored in in vivo studies is the mechanical forces and cues that control collective cell migration. Thus, while the role of molecular signals in collective cell migration is comparatively well understood, how tissue mechanics influences this cluster migration in vivo remains unknown. Here we will analyse the role that mechanical cues play during in vivo collective cell migration of neural crest cells, an embryonic cell type, whose migratory behaviour has been likened to cancer metastasis. We will characterize the mechanical properties of the substrate used by neural crest cells during migration, and test the hypothesis that the onset of collective cell migration as well as its directionality is controlled by mechanical cues. In addition, we will study the interplay between mechanical and chemical cues during cell migration and analyse the molecular bases of in vivo mechanosensing.
This multidisciplinary project will combine the expertise on in vivo collective cell migration and biomechanics from the two participating teams, and it will have wide implications for many areas where cell migration is important, such as cell and developmental biology, cancer biology, biophysics and bioengineering.

In this collaborative multi-disciplined project, we identify the international science base and the general public as beneficiaries beyond the immediate academic community. Expert training of the appointees will contribute directly to the science base. We aim to identify the mechanism by which physical cues control neural crest migration during normal development. Failure of neural crest migration leads to a wide range of syndromes called neurocristopathies, which represent an important fraction of birth defects in England (1.1%; UK Health Research). To achieve maximal impact of the research, we will provide a broad range of scientific training through the combination of internationally recognized expertise bought by the applicants. In addition, professional training will be ensured through the infrastructure provided by the world-class universities in which the research will be performed. We will engage the public through the UCL facilities to communicate and disseminate our discoveries to the general public. In addition to interactions with the general media, lay publications and outreach activities aimed at school children. We are currently interacting with a private company to develop video games based on movement of cells that could relate to the general public. We will continue with this kind of activities to ensure that our research will provide major impact in several disparate areas.