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::Nras^Q61K 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.