Claudia Wellbrock, Habilitation, PhD
Melanoma skin cancer
Melanoma skin cancer is one of the most rapidly increasing cancers worldwide and highly fatal if excision fails to cure the patient. This is in great part due to the very early tendency of melanoma cells to spread throughout the body and to be resistant to cytotoxic chemotherapeutics. It is thought that this behaviour is intrinsic to melanoma cells as they originate from melanocytes, whose nature it is to be motile and ‘cytotoxic damage’-resistant.
Melanocytes are highly specialised cells that are found at the boarder of the epidermis with the dermis. Under physiological conditions, melanocytes act as a protective shield against harmful UV rays in a process called the tanning response. Sun exposure triggers the production of the pigment melanin by melanocytes, and this melanin is transferred to the surrounding cells in the epidermis -the keratinocytes- in order to protect them from UV induced damage. On the other hand keratinocytes secrete factors that ensure that melanocytes stay localised within the epidermis, and that differentiation is favoured over cell division.
In order to function within this symbiotic relationship an accurate communication between melanocytes and keratinocytes is absolutely essential and direct cell-cell contact is a prerequisite for this communication. Any disturbance of the melanocyte-keratinocyte interaction can create a pathological situation with deregulated melanocyte proliferation and the transformation into malignant melanoma cells. These malignant melanoma cells have a high potential to invade a ‘foreign’ tissue environment, and to spread and eventually colonise to distant sites, where they form secondary tumours.
In order to help improving current strategies for the treatment of melanoma, we are studying the biology underlying melanocyte transformation and melanoma cell spreading. This includes the process of deregulated melanocyte-keratinocyte interactions that triggers melanocyte transformation, as well as the mechanisms behind the particular motility of melanoma cells within an altered tissue and thus matrix environment.
The scientific story
Melanoma skin cancer is one of the most rapidly increasing cancers worldwide and highly fatal if excision fails to cure the patient. This cancer originates from melanocytes, highly specialised cells that are found at the basal membrane of the epidermis within the skin. Already early on during melanoma development transformed cells display an altered communication with their microenvironment and adopt changes in adhesion-dependent differentiation, proliferation, survival and motility. Compared to other skin cancers, such as squamous cell or basal cell carcinoma melanoma shows a notoriously high potential for invasion and eventually colonisation to distant sites. It is thought that this high potential to invade a different tissue environment, and to spread and survive at distant sites within the body is intrinsic to melanoma cells as they originate from melanocytes, whose nature it is to be motile and ‘stress’-resistant cells.
The particular features of melanocytes and melanoma allow us to investigate two crucial aspects of cancer-cell signaling that can be target for intervention: The cellular signalling that directs cancer-type specific behaviour, and the signalling that controls the communication of tumour cells with the tumour-microenvironment.
We are addressing these aspects by studying cellular signalling in vitro in reconstituted cell-culture models. In particular we are investigating the role of the melanoma specific fate-decision regulator MITF (Microphthalmia transcription factor), and its link to e.g. Src kinases, Wnt/beta-catenin signalling and the ERK/MAP kinase pathway. Furthermore, in collaboration with Dr Adam Hurlstone (molecular cancer studies) we have established in vivo tumour-xenograft assays in zebrafish in order to perform live-imaging of individual migrating and invading melanoma cells. This system will also allow us to analyse the effect of anti-neoplastic drugs on the behaviour of these notoriously invasive tumour cells in vivo.
With our work we hope to help improving current strategies for the treatment of melanoma by verifying and identifying therapeutic targets and prognostic markers.
Tel: +44 (0) 161 275 5189
Recent key publications
Smith, M., Ferguson, J., Arozarena, I., Hayward, R., Marais, R., Chapman, A., Hurlstone, A. and Wellbrock, C. (2013) Effect of SMURF2 Targeting on Susceptibility to MEK Inhibitors in Melanoma. JNCI. 105, 33-46. PMC
Ferguson, J., Arozarena, I., Ehrhardt, M., Wellbrock, C. (2012). Combination of MEK and SRC inhibition suppresses melanoma cell growth and invasion. Oncogene 32, 86-96. PubMed
Arozarena, I., Bischof, H., Gilby, D., Belloni, B., Dummer, R., and Wellbrock, C. (2011) In melanoma, beta-catenin is a suppressor of invasion. Oncogene 30, 4531-43. PubMed.