Abstract B147: P-Rex1 is required for efficient melanoma metastasis.

Abstract

Abstract Background: P-Rex1 is a Rac-specific Rho GTPase guanine nucleotide exchange factor that has recently been implicated in cancer for the first time. As Rac has a central role in control of cell motility, we assessed the role of P-Rex1 in melanoma, a cancer where metastasis is the major cause of death. This was the first evaluation of P-Rex1 in a genetically modified animal model of cancer. We also investigated the function of P-Rex1 in melanoblasts, as the molecular pathways that drive their developmental migration are believed to underpin the movement of metastatic melanoma cells. Methods: P-Rex1−/− mice were crossed to mice carrying the DCT-lacZ transgene, a melanoblast reporter line, and a Tyr::NrasQ61K/°; INK4a−/− metastatic melanoma mouse model. Allograft tail vein (TV) injections were performed to further assess the endogenous function of P-Rex1 in metastasis. Panels of human melanoma cell lines and tissue were investigated with microarray, tissue culture, and immunohistochemical techniques. Results: P-Rex1−/− mice have a melanoblast migration defect during development (p=0.01), evidenced by a white belly. They were resistant to metastasis when crossed to the Tyr::NrasQ61K/°; INK4a−/− murine model of melanoma (1/30 mice with metastases vs 13/30 in control cohort; p=0.001). When melanocytes derived from this model were TV-injected into immune-competent allografts, endogenous P-Rex1 was found to facilitate metastatic incidence, growth, and organ spread following the intravasation stage of the metastatic cascade (p=0.02). Mechanistically, this was associated with P-Rex1 driving invasion in a Rac-dependent manner. In humans, P-Rex1 was elevated in the great majority of melanoma cell lines, with mRNA levels above the median statistically associated with metastasic propensity (p=0.005). Tissue immunohistochemistry revealed an association between tumor progression and P-Rex1 expression. Conclusions: P-Rex1 is a key component of melanoma progression, invasion and metastatic signaling, supporting the value of pharmacological inhibition of P-Rex1 activation of Rac for treatment of metastatic or high risk primary melanomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B147.