OPTOLEADER · Optogenetic control of leader cell mechanobiology during collective cell migration

Optogenetic control of leader cell mechanobiology during collective cell migration

Within the human body, the concerted and coordinated movement of cells is a recurring phenomenon of key importance for understanding both health and disease. For example, cells collectively migrate during embryo development and precisely form the body’s complex shapes; similarly, cells move cohesively to efficiently heal wounds and to maintain vital organ and tissue functions. Comparable mechanisms are at play also during cancer progression, when tumour cells employ collective migration strategies to invade healthy tissue and to drive metastasis. These are fundamentally important biophysical processes, and in the last two decades experimental and theoretical studies have uncovered that they are driven by cell-generated forces. In this context, the mechanical interactions of specific subgroups of cells known as “leader cells” is particularly important, albeit little understood. These cells are thought to dynamically guide a collectively migrating group, by exerting forces on their neighbours and on their surroundings, by reacting to chemical cues and by having well-defined directionality. In our project, called OPTOLEADER, we aimed to understand at a fundamental level how mechanical interplay between leaders and other cells gives rise to and affects collectively migrating groups. Our main approach was to use genetically engineered cells whose motility can be controlled by light with high precision and no damage to the cells. With these cells we can induce leader-like behaviour at will, using a microscope to both deliver the light stimulation and to observe the cells’ behaviour. We combined these experiments with a powerful technique called Traction Force Microscopy (TFM) that allows us to measure the forces exerted by the cells while they migrate, with high spatial and temporal resolution. We employed this approach to generate leaders within cell groups and set out to discover if and how mechanical interactions allow them to guide collective migration. As is often the case, the results of the experiments revealed a much more complex and nuanced picture than was previously believed. OPTOLEADER showed that the long-held notion that leader-cells are the initiators and drivers of collective migration is an oversimplification. In fact, apparent leadership effects in migrating cells can be effectively viewed as a consequence of collective behaviours of the “followers” working together with the leaders. This coordination between the cells is a mechanical phenomenon and is brought about by the way tension is built-up and redistributed within a cohesive group of cells. We believe that these results will shed new light on essential biophysical processes that are key to understand organism growth and development, tissue mechanics and tumour progression.

Data: CORDIS, © European Union