The Neural Crest as a new paradigm to study Contact inhibition of Locomotion in vivo: role of Wnt and Ephrin signalling

Metastasis is the process by which cancer cells disperse from the original tumour and move away to colonize a new host tissue, where the tumor cells proliferate and generate a secondary tumor. Most of the deaths caused by cancer are dependent on this metastatic process and not on the primary tumor. The molecular bases of this cell dispersion process are not completely understood.
Neural Crest is an embryonic population of cells originated in the dorsal region of the embryo from where it disperse and colonize many tissues of the embryo, in a process that has been likened to metastasis of tumor cells.
In this project we propose to analyze the dispersion of neural crest cells during normal embryonic development. We propose a new mechanism for this process based in Contact Inhibition. Briefly, when two cells meet they stop migrating and move away from each other. We propose to study the chemical signals that control the interaction and the response of this repulsive reaction between cells. We will analyze the migration of the neural crest in live fish embryos as they are very accessible for live imaging and in neural crest cultured in vitro taken from frog embryos as they are very easy to manipulate.
The results will help us to understand the molecular and developmental causes underlying human disease, such as cancer and others, and in the longer term is likely to lead to new diagnostic tools.

In the UK during 2005 there were 153,491 deaths from cancer. Most of these deaths were not caused by the primary tumor but by the metastasis and colonization of a new host tissue. Although considerable progress has been made in understanding the process of metastasis, it still offers the greatest challenge for the clinical management and treatment of cancer. More than 50 years ago Abercrombie proposed that one of the causes of metastatic invasion was related to the loss of Contact Inhibition among the cancer cells. However, the molecular basis of contact inhibition and whether it also occurs in vivo are still unknown. Our recent work, supported by the MRC, has allowed us to develop a system where Contact Inhibition can be studied in vivo. This system corresponds to the migration of Neural Crest (NC) cells during embryo development, a process likened to malignant invasion (Kuriyama and Mayor, 2008).
Contact Inhibition was initially used to describe the behaviour of fibroblast cells confronting each other in vitro, where they retract their protrusions and change direction upon contact. Our preliminary studies suggest that NC exhibit Contact Inhibition (CI) and that this process depends on the non-canonical/PCP and Eph/ephrin signaling. We propose here that migration of NC in vivo from a region of high cell density in the dorsal neural tube to areas of lower cell density close to the NC targets is dependent on CI.
In this project we will analyze whether NC cells exhibits CI in vitro and in vivo; we will generate a computational modelling of CI to show how this phenomena can generate directional migration of a cell population and we will explore the molecular basis of CI.
Live-imaging techniques of transgenic fishes that express fluorescent proteins in the neural crest will be used to study cell migration in vivo. By gain and loss function experiments we will investigate the role and the interaction of non-canonical Wnt and Eph/ephrin signalling in CI. The data generated in this project will help us to understand the molecular bases of contact inhibition; which happens in normal and in cancer cells.