巴黎萨克雷大学Véronique Delmas小组的一项最新研究开发出靶向GRPR治疗E-钙粘蛋白缺失后的性激素依赖性癌症。这一研究成果发表在2025年6月11日出版的国际学术期刊《自然》上。

该团队发现绝经前女性对癌症的易感性增加，该团队发现细胞-细胞粘附分子E-钙粘蛋白是各种癌症（包括黑色素瘤）雌激素反应的关键成分。在黑色素瘤的小鼠模型中，该团队发现了一条雌激素致敏通路，连接E-cadherin、β-catenin、雌激素受体-α和GRPR，促进女性黑色素瘤的侵袭性。通过靶向GRPR或雌激素受体-α抑制该途径可减少小鼠的转移，表明其治疗潜力。他们的研究引入了一个将激素敏感性和肿瘤表型联系起来的概念，其中激素影响细胞表型和侵袭性。研究人员已经在女性中发现了一个整合的促肿瘤途径，并提出针对G蛋白偶联受体的药物通常不用于癌症治疗，可以更有效地治疗女性E-钙粘蛋白依赖性癌症。这项研究强调了性别特异性因素在癌症管理中的重要性，并为改善各种癌症的预后提供了希望。

据介绍，性别在癌症方面的不平等是有据可查的，但目前有限的认识阻碍了精准医学和治疗的进步。考虑种族、年龄和性别对癌症患者的管理至关重要，因为它们是发病率和治疗反应的重要差异的基础。与年龄相关的激素产生在性别之间是一致的差异，在不被认为是激素依赖的癌症中被低估了。

附：英文原文

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

Author: Raymond, Jrmy H., Aktary, Zackie, Pouteaux, Marie, Petit, Valrie, 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, Batrice, Larue, Lionel, Delmas, Vronique

Issue&Volume: 2025-06-11

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 dependent4,5,6. 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, 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.

DOI: 10.1038/s41586-025-09111-x

Source: https://www.nature.com/articles/s41586-025-09111-x