Targeting GRPR for sex hormone-dependent cancer after loss of E-cadherin

Jérémy H. Raymond, Zackie Aktary, Marie Pouteaux, Valérie Petit, Flavie Luciani, Maria Wehbe, Patrick Gizzi, Claire Bourban, Didier Decaudin, Fariba Nemati, Igor Martianov, Irwin Davidson, Catherine-Laure Tomasetto, Richard M. White, Florence Mahuteau-Betzer, Béatrice Vergier, Lionel Larue () and Véronique Delmas
Additional contact information
Jérémy H. Raymond: INSERM U1021
Zackie Aktary: INSERM U1021
Marie Pouteaux: INSERM U1021
Valérie Petit: INSERM U1021
Flavie Luciani: INSERM U1021
Maria Wehbe: INSERM U1021
Patrick Gizzi: Strasbourg University/Strasbourg Drug Discovery and Development Institute (IMS)
Claire Bourban: Strasbourg University/Strasbourg Drug Discovery and Development Institute (IMS)
Didier Decaudin: PSL University Paris
Fariba Nemati: PSL University Paris
Igor Martianov: Université de Strasbourg
Irwin Davidson: Université de Strasbourg
Catherine-Laure Tomasetto: Université de Strasbourg
Richard M. White: University of Oxford
Florence Mahuteau-Betzer: Université PSL
Béatrice Vergier: INSERM/Université de Bordeaux
Lionel Larue: INSERM U1021
Véronique Delmas: INSERM U1021

Nature, 2025, vol. 643, issue 8072, 801-809

Abstract: Abstract Sex inequalities in cancer are well documented, but the current limited understanding is hindering advances in precision medicine and therapies1. Consideration of ethnicity, age and sex is essential for the management of cancer patients because they underlie important differences in both incidence and response to treatment2,3. Age-related hormone production, which is a consistent divergence between the sexes, is underestimated in cancers that are not recognized as being hormone dependent4–6. Here, we show that premenopausal women have increased vulnerability to cancers, and we identify the cell–cell adhesion molecule E-cadherin as a crucial component in the oestrogen response in various cancers, including melanoma. In a mouse model of melanoma, we discovered an oestrogen-sensitizing pathway connecting E-cadherin, β-catenin, oestrogen receptor-α and GRPR that promotes melanoma aggressiveness in women. Inhibiting this pathway by targeting GRPR or oestrogen receptor-α reduces metastasis in mice, indicating its therapeutic potential. Our study introduces a concept linking hormone sensitivity and tumour phenotype in which hormones affect cell phenotype and aggressiveness. We have identified an integrated pro-tumour pathway in women and propose that targeting a G-protein-coupled receptor with drugs not commonly used for cancer treatment could be more effective in treating E-cadherin-dependent cancers in women. This study emphasizes the importance of sex-specific factors in cancer management and offers hope of improving outcomes in various cancers.

Date: 2025
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DOI: 10.1038/s41586-025-09111-x

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