The E-cadherin-ESR1-GRPR axis defines a sex-specific metastatic pathway in melanoma

Although tremendous progress has been made in understanding the mechanisms leading to cancer, those governing metastases are still poorly understood. E-cadherin (Ecad) is a cell-cell adhesion molecule essential for tissue homeostasis, and its loss often correlates with the dissemination of human cancers. However, whether and how the loss of Ecad triggers the full metastatic program is largely unknown. Here, we show that the loss of Ecad promotes melanoma lung metastases in females. The loss of Ecad, after the induction of estrogen receptor α (ERα) expression, activates gastrin-releasing peptide receptor (GRPR) expression. GRPR promotes cellular processes essential for metastasis formation through Gaq and YAP1 signaling and its pharmacological inhibition reduces metastasis in vivo. This study reveals an Ecad-ERα-GRPR metastatic sex dimorphism axis in melanoma that is conserved in human breast cancer and provides proof of concept that the G-coupled receptor GRPR is a therapeutic target for metastasis.