Dalton, L.E., Kamarashev, J., Ramirez, I.R., White, G., Malliri, A., and Hurlstone, A. (2013) Constitutive Rac Activation is not Sufficient to Initiate Melanocyte Neoplasia but Accelerates Malignant Progression. The Journal of investigative dermatology. 133(6):1572-81.
Deregulated Ras signalling initiates and maintains melanocyte neoplasia. The Rho-like GTPase Rac has been implicated in Ras-induced neoplastic transformation. Moreover, a recurrent UV-induced mutation activating RAC1 has recently been detected in human melanoma. Here, a role for Rac in melanoma initiation and progression was investigated in human melanomas and zebrafish models of melanocyte neoplasia. Immunohistochemical analysis revealed RAC expression and activity restricted to melanocytes at the junction of the epidermis and dermis in benign neoplasms. Malignant melanocytes displayed elevated RAC activity that extended into the suprabasal epidermis, deeper into the dermis, and was maintained in metastases. Previously, we have used zebrafish transgenic models to demonstrate that deregulated Ras-Raf-Mapk signalling can initiate melanocyte neoplasia. Expression of a constitutively active RAC1 mutant (V12RAC1) was not sufficient to initiate melanocyte neoplasia in this organism. Further, we did not detect an additive effect when combined with V600EBRAF; nor could V12RAC1 substitute for suppressed Pi3k signalling to restore melanoma progression. However, co-expression of V12RAC1 and oncogenic RAS accelerated tumour nodule formation. Immunohistochemical analysis revealed that the Rac activator Tiam1 is overexpressed in melanoma tumour nodules both in zebrafish and man. Thus our data suggest that Rac contributes to the progression of melanoma and that Tiam1 may activate Rac in nodular presentations.