ACP McElwain Prize: P-Rex1 is a central component of metastasis in malignant melanoma


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Colin Lindsay1,Samuel Lawn1,William Faller1,Andrew Campbell1,Channing Der2,Kate Pedone2,Heidi Welch3,Lionel LaRue4,Iain Jackson5,Friedrich Beerman6,Brad Ozanne1,Owen Sansom1
1The Beatson Institute for Cancer Research, Glasgow, UK,2The University of North Carolina, Chapel Hill, USA,3The Babraham Institute, Cambridge, UK,4Centre de Recherche, Institut Curie, Paris, France,55MRC Human Genetics Unit, Edinburgh, UK,6ISREC, Epalinges, Switzerland

Background

P-Rex1 is a guanine nucleotide exchange factor responsible for activation of Rac by promoting its GTP-bound form. Tissue culture work has revealed P-Rex1 to have a central role in cell motility and invasion, processes thought to be crucial to the development of metastases. It was also found to be consistently up-regulated in a panel of melanoma cell lines.

Method

We initially noted that P-Rex1 knockout mice exhibit a characteristic ‘white belly’ phenotype with accompanying white feet. We used the Dct-lacZ reporter transgene to mark cells of the melanoblast lineage, showing that this phenotype is predominantly accounted for by a melanoblast migration defect at embryogenesis rather than a proliferative disorder. As significant parallels have been highlighted between melanoblast migration in embryogenesis and invasive melanocyte migration during malignant melanoma metastasis, we tested whether P-Rex1 is a central component of movement in melanoma cell metastasis. P-Rex1 wild-type and knockout mice were crossed to a melanoma mouse model (Tyr::NrasQ61K INK4a-/-) which genetically recapitulates the human disease, characteristically developing primary melanomas at 6 months and visceral metastases in approximately 33% of cases. Consistent with our in vitro work, P-Rex1 knockout did not delay onset or size of primary melanoma but highly significantly reduced incidence of melanoma metastases compared to P-Rex1 wild-type mice. In particular, incidence of brain tumours was notably reduced. P-Rex1 also showed immunoreactivity in primary and metastatic tumours from both mice and humans.

Results

Conclusion

P-Rex1 is a potential novel target for anti-metastatic therapeutic intervention in malignant melanoma.