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

• 成果类型: Article
• 署名作者: Raymond, Jeremy H.; Aktary, Zackie; Pouteaux, Marie; Petit, Valerie; Luciani, Flavie; Wehbe, Maria; Gizzi, Patrick; Bourban, Claire; Decaudin, Didier; Nemati, Fariba; Martianov, Igor; Davidson, Irwin; Tomasetto, Catherine-Laure; White, Richard M.; Mahuteau-Betzer, Florence; Vergier, Beatrice; Larue, Lionel; Delmas, Veronique
• 署名单位: Universite PSL; UNICANCER; Institut Curie; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Saclay; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite Paris Saclay; Universite PSL; UNICANCER; Institut Curie; Institut National de la Sante et de la Recherche Medicale (Inserm); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; UNICANCER; Universite PSL; Institut Curie; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Institut National de la Sante et de la Recherche Medicale (Inserm); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; University of Oxford; Ludwig Institute for Cancer Research; UNICANCER; Universite PSL; Institut Curie; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Saclay; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Chemistry (INC); Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Chemistry (INC); Universite Paris Saclay; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Bordeaux; CHU Bordeaux; Universite de Bordeaux; Institut National de la Sante et de la Recherche Medicale (Inserm)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2985
• DOI: 10.1038/s41586-025-09111-x
• 发表日期: 2025-07-17
• 关键词: gastrin-releasing-peptide; estrogen-receptor; expression; activation; package; tumorigenesis; suppression; mutations; complex; binding

摘要

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, 5-6. 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, beta-catenin, oestrogen receptor-alpha and GRPR that promotes melanoma aggressiveness in women. Inhibiting this pathway by targeting GRPR or oestrogen receptor-alpha 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.