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

Auteurs

Jérémy H. Raymond, Marie Pouteaux, Valérie Petit, Zackie Aktary, Flavie Luciani, Maria Wehbe, Patrick Gizzi, Claire Bourban, Igor Martianov, Irwin Davidson, Catherine-Laure Tomasetto, Florence-Mahuteau Betzer, Béatrice Vergier, Lionel Larue, Véronique Delmas

Résumé

Summary

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 G□qand YAP1 signaling and its pharmacological inhibition reduces metastasisin 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.

Membres

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VALERIE PETIT

Ingénieur de recherche

LIONEL LARUE

Directeur de recherche Inserm