July 2013 - present
Senior Lecturer, University of Manchester
July 2010 - July 2013
Lecturer, University of Manchester
July 2004 - June 2010
Cancer Research UK Career Development Fellow, University of Manchester
Post-doctoral research associate in the lab. of Hans Clevers, Academic Hospital Utrecht and Hubrecht Laboratories, The Netherlands
PhD University of Glasgow, Faculty of Medicine. Research performed at CR-UK Beatson laboratories under the supervison of Dr Donald M. Black
BA (Hons) University of Cambridge, Natural Sciences.
Melanoma is an aggressive type of skin cancer that is caused by excessive sunlight transforming cells in our skin from helpful cells that produce a tan (melanocytes) to potential killers. My laboratory is studying this process of transformation so that we can diagnose it more easily and rapidly as well as design therapies that prevent, delay or if necessary reverse change.Together with tissue culture models, we use Zebrafish, a small tropical fish common in many households as a pet, to study this process. Zebrafish too have melanocytes (they make up their stripes) and, as our research has shown, can also develop melanoma. Now Zebrafish are giving us insight into melanoma as well as opportunities for finding new, more effective treatments.
The main focus of my group is melanoma tumour biology. In particular, we focus on factors underlying malignant conversion of melanocytes. Along with tissue culture models, we use the zebrafish as a model organism, manipulating this organism through mutagenesis, transgenesis, antisense oligonucleotides, and small molecule inhibitors. Using these methods, we have developed melanoma models and are now validating the role of certain genes (implicated through transcription profiling and data mining) as therapeutic targets.
To illustrate our strategy, we have recently targeted expression of human oncogenic RAS to zebrafish melanocytes. This has given rise to a model of melanoma, both sporadic and familial. At the same time through expressing oncogenic BRAF, we have generated a model of benign melanocyte neoplasia. Moreover, through simultaneously expressing RAS and an inhibitor of the PI3K signalling pathway (a truncated form of the PI3K regulatory protein p85), we have demonstrated the importance of PI3K signalling in the progression of melanocyte neoplasia to malignancy. Comparing the transcriptomes of melanocytes with these different genotypes is revealing interesting patterns of diffferential gene expression that correlate with disease state. Analysis of these altered states of gene expression is implicating deregulated developmental signalling and inflammation in melanoma disease progression.
The above gene expression analysis is also supplying us with candidates to pursue to target melanoma. We have demonstrated that melanoma initiates in RAS-expressing animals soon after fertilisation. At this time-point animals are very amenable to targeted knockdown of gene products using both antisense oligonucleotides as well as small molecule inhibitors. We have developed a simple, sensitive and robust spectrophotometric assay for quantifying the extent of neoplasia in transgenic larval zebrafish, and have demonstrated that targeted knockdown of MAPK, PI3K and TOR signalling components antagonizes melanoma development. Reversing the logic of this approach implies that this in vivo assay could be used to discover novel antineoplastic compounds, something we would like to demonstrate in the near future.