New Sex-Specific Pathway Uncovered in Melanoma Metastasis with Implications for Female Cancer Therapies

Researchers at the Institut Curie have identified a fascinating sex-specific molecular pathway that significantly influences melanoma metastasis, especially in women. This pathway involves the loss of the cell adhesion molecule E-cadherin, which triggers a cascade involving estrogen receptor-alpha (ERα) and the gastrin-releasing peptide receptor (GRPR), ultimately promoting the spread of melanoma cells. Their study, published in Nature, employed an extensive mouse model where melanoma was induced with a conditional deletion of the Cdh1 gene (coding for E-cadherin) alongside a mutation in NRAS. Interestingly, while primary tumor development was similar regardless of sex or E-cadherin status, female mice lacking E-cadherin showed a remarkable increase in lung metastases—reaching 63% compared to 16% in females with intact E-cadherin. This highlights E-cadherin's role in suppressing metastatic progression specifically in females.

Further investigations revealed that the loss of E-cadherin led to a notable overexpression of GRPR in melanoma cells, primarily in females. Activation of GRPR was shown to promote tumor growth and metastasis by engaging the YAP1 pathway, which enhances cell invasiveness and survival. Pharmacological blockade of GRPR with RC-3095 significantly reduced lung metastases, suggesting it as a promising therapeutic target. Additionally, the research uncovered a feedback loop where E-cadherin loss activates β-catenin, which then promotes ESR1 gene expression, increasing ERα levels. ERα, in turn, boosts GRPR expression, establishing a sex-specific, hormone-related metastatic pathway.

Remarkably, the study demonstrated that using Fulvestrant, an ERα inhibitor approved for breast cancer, effectively suppressed melanoma invasion and spread in the model. These findings indicate that drugs targeting hormonal pathways, traditionally used in hormone-dependent cancers, could be repurposed to treat melanoma in women. Overall, this research points to the importance of understanding sex-specific molecular mechanisms in cancer progression, paving the way for more personalized and effective therapies for melanoma and potentially other cancers affecting women.