425 GRPR is an effective target for melanoma

While tremendous progress has been made in the understanding of the mechanisms leading to cancers, the understanding of the mechanisms governing the formation of metastases remains poorly understood. The cell-cell adhesion protein E-cadherin (E-cad) has been associated with the metastatic development of melanoma, but the mechanisms have not yet been described nor has the actual impact of E-cad been evaluated. Here, using a novel mouse model expressing the oncogenic form NRASQ61K in melanocyte, we show that the conditional deletion of Cdh1 (which encode E-cad) does not influence melanoma initiation but dramatically promotes metastases. Interestingly, loss of Cdh1 induces intensely the expression of the Gastrin-releasing peptide receptor (Grpr) belonging to the G protein-coupled receptor family. Activation of GRPR induces major cellular processes of tumor progression such as cell growth, clonogenicity, resistance to anoikis, and cell invasion and migration. At the molecular level, GRPR activation promotes the activation of the transcription factor YAP1, involved in melanoma metastasis. Furthermore, induction of GRPR expression induces the ability of human and murine cells to colonize mouse lungs after injection of the cells into the tail vein of mice. Targeting GRPR with the GRPR antagonist, RC-3095, drastically decreases the formation of melanoma metastases after injection of cells into the tail vein of mice. Therefore, our study highlights the importance of the newly discovered E-cad/GRPR axis in melanoma progression. Moreover, our results propose GRPR targeting as a new therapeutic option in treating melanoma metastases.