Sex-specific pathway driving melanoma metastasis discovered, with implications across female cancer treatments

Institut Curie researchers have identified a sex-specific molecular pathway connecting E-cadherin loss, estrogen receptor-α (ERα), and GRPR, contributing significantly to increased melanoma metastasis in women.

Sex-based disparities in cancer are widely recognized, with men generally showing higher cancer incidence overall. Premenopausal women face heightened vulnerability to certain cancers, notably malignant melanoma, suggesting potential hormone-related pathways that are poorly understood and largely neglected in treatment strategies.

In the study, "Targeting GRPR for sex hormone-dependent cancer after loss of E-cadherin," published in Nature, researchers designed experiments to elucidate the role of estrogen and the adhesion molecule E-cadherin in cancer metastasis.

Employing an extensive mouse model of melanoma, the research team induced melanoma with conditional deletion of the E-cadherin gene (Cdh1) alongside a cancer-promoting NRAS mutation. They compared melanoma development and progression in mice with and without functional E-cadherin, across sexes.

Results showed no difference in initial melanoma onset or primary tumor growth. Yet notably, female mice lacking E-cadherin exhibited significantly higher lung metastasis (63%) compared with female mice retaining E-cadherin (16%), indicating E-cadherin's critical role in preventing metastatic spread specifically in females.

Loss of E-cadherin markedly increased expression of the gastrin-releasing peptide receptor (GRPR), a G-protein-coupled receptor. GRPR was uniquely overexpressed in E-cadherin-deficient female melanoma cells, with data supporting GRPR involvement in facilitating or accelerating melanoma metastasis.

Artificially introducing GRPR to melanoma cells independently induced metastases in mice. Importantly, blocking GRPR with a pharmacological antagonist, RC-3095, reduced lung metastases, validating the receptor as a potential therapeutic target.

Mechanistically, researchers established a direct link between GRPR activation and YAP1, a protein known to promote cancer cell invasiveness and survival. Activated GRPR increased cell growth, resistance to cell death (anoikis), and invasiveness—all key processes required for metastasis. Conversely, inhibiting GRPR or associated pathways effectively reversed these tumor-promoting traits.

Further investigation revealed how loss of E-cadherin triggers GRPR overexpression. In normal cells, E-cadherin restricts the transcriptional activity of β-catenin.

When E-cadherin is lost, β-catenin activates the ERα gene (ESR1), whose protein indirectly enhances GRPR expression. This creates an amplifying feedback loop where activated GRPR further suppresses E-cadherin, escalating tumor aggressiveness.

Critically, researchers tested an ERα inhibitor already used in breast cancer treatments (Fulvestrant), demonstrating effective suppression of GRPR-mediated melanoma invasion and metastasis.

The findings suggest that drugs traditionally employed in hormonal cancers may be beneficial in treating melanoma and potentially other cancers in women.

Authors conclude that E-cadherin loss sets off a distinct, sex-specific pathway through ERα and GRPR, significantly driving cancer aggressiveness and metastasis in women. Findings point to sex-specific molecular pathways as a way to improve precision medicine, presenting new therapeutic avenues, particularly for cancers traditionally considered hormone-independent.

Written for you by our author Justin Jackson, edited by Sadie Harley , and fact-checked and reviewed by Robert Egan —this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You'll get an ad-free account as a thank-you.

More information: Jérémy H. Raymond et al, Targeting GRPR for sex hormone-dependent cancer after loss of E-cadherin, Nature (2025). DOI: 10.1038/s41586-025-09111-x

Svenja Meierjohann, Sex differences in skin-cancer risk are linked to oestrogen levels, Nature (2025). DOI: 10.1038/d41586-025-01708-6

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This article was originally published on MedicalXpress Breaking News-and-Events.