The role of supracellular actomyosin in collective cell migration in vivo

One of the most devastating diseases is cancer, which we still do not fully understand or are able to control. Cancer cells exhibit many of 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 cellular and molecular mechanisms driving these processes may be similar. We will study the mechanisms controlling migration during development. We have chosen the cephalic neural crest cells as an example from embryonic development, as they are perfectly suited for cell migration studies in vivo and because they play a major role in craniofacial development. Importantly, craniofacial disorders are a primary cause of infant mortality and have serious lifetime consequences, devastating for both children and parents.

We will test the novel hypothesis that when a group of cells migrates towards a chemical signal the cells located at the back, instead of the front cells, are the ones that generate the force for the movement of the whole cell cluster. We expect that the new understanding of cell migration generated here will be useful to design novel therapeutic approaches in cancer and craniofacial malformation.

Cell migration is essential for development, adult homeostasis and cancer invasion. It has been recognized that cells often migrate in groups and not only as single cells. This collective migration of cells has become an intense area of research in Cell, Developmental and Cancer Biology, as it is essential for both morphogenesis and cancer invasion. However the molecular mechanisms behind this phenomenon are still unclear.

It has been assumed that leader cells are the ones that actively drag the trailing cluster and therefore most of the efforts have focused on the front. The alternative explanation that trailing cells drive cluster movement is counterintuitive and would be equivalent to the proverb "putting the cart before the horse". Surprisingly, our exciting preliminary evidence suggests just that. Therefore in this project we will test the challenging idea that collective chemotaxis is driven by the back cells ("cart") making the rest of the cells ("horse") move forward.

Specifically, we will test the central hypothesis that a supracellular actomyosin ring contracts at the back of the cluster driving the group forwards. To do this we aim to establish:
1) The significance of actomyosin contractility at the back of the cluster
2) The cellular dynamics by which contractility promotes collective chemotaxis
3) The mechanism by which adjacent cells coordinates their contractility

We will use Xenopus neural crest for our in vivo developmental studies. Should our hypothesis prove correct, it has the potential to fundamentally change the current view on collective cell migration. Regardless, however, our findings will have far reaching implications not only in morphogenesis and cancer invasion, but in a multitude of other related biological phenomena.

In this project we identify the international science base and the general public as beneficiaries beyond the immediate academic community.

Professional and technical training of the PDRA to be appointed on the project will contribute directly to the science base. To achieve maximal impact of the research, we will provide a broad range of scientific training through the combination of internationally recognized expertise brought by the applicants. In addition, professional training will be ensured through the infrastructure provided by the collaborating world-class universities in which the research will be performed.

We aim to identify the mechanism that controls collective migration of neural crest cells during normal development. We hope to raise awareness to our research among the general public as 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). 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, we plan to produce 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.