Characterising the role of cell-cell adhesion in melanoma development

Malignant melanoma accounts for over 85% of all skin cancer deaths, mainly due to resistance against conventional chemotherapies and an early acquisition of invasive behaviour. During melanoma development transformed cells display an altered communication with their microenvironment and adopt changes in adhesion-dependent differentiation, proliferation, survival and motility. This facilitates uncontrolled tumour cell proliferation within the epidermis, invasion into the dermis and eventually colonisation to distant sites.

In order to dissect signalling events relevant for melanoma cell invasion, we have investigated the role of cadherins and catenins because they are main regulators of cell-cell adhesion and interactions with the extracellular environment. We discovered novel roles for beta-catenin and p120-catenin in melanoma cell proliferation and invasion and now want to further characterise their function in melanoma development. This includes studying their interaction with different cadherins (E-cadherin in normal cells, N-cadherin in invasive cells), dissecting the mechanism by which they regulate proliferation, and how they contribute to cell survival when cells cannot make cell-cell contact (a situation found when cells disseminate and give rise to circulating tumour cells and distant metastasis). If we can better understand how these proteins function, we can identify drugs that will allow interfering with their role in melanoma development.

The project will use cell signalling inhibitors and RNAi approaches in cell-culture, and live-cell imaging in three-dimensional (3D) culture systems and in vivo in zebrafish models, where cell invasion, dissemination into the bloodstream and distant seeding of cancer cells can be visualized. Overall, the project provides a unique opportunity to acquire knowledge in a wide range of protein-biochemical, cell-biological and imaging techniques related to translational cancer research.