Role of the androgen receptor in melanoma aggressiveness
Abstract Malignant melanoma represents the fifth most common cancer in the world and its incidence is rising. Novel therapies targeting receptor tyrosine kinases, kinases and immune checkpoints have been employed with a significant improvement of the overall survival and long-term disease containmen...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-01-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07350-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832585381731631104 |
|---|---|
| author | Marzia Di Donato Costanza Maria Cristiani Mariaelena Capone Cinzia Garofalo Gabriele Madonna Lucia Carmela Passacatini Margaret Ottaviano Paolo Antonio Ascierto Ferdinando Auricchio Ennio Carbone Antimo Migliaccio Gabriella Castoria |
| author_facet | Marzia Di Donato Costanza Maria Cristiani Mariaelena Capone Cinzia Garofalo Gabriele Madonna Lucia Carmela Passacatini Margaret Ottaviano Paolo Antonio Ascierto Ferdinando Auricchio Ennio Carbone Antimo Migliaccio Gabriella Castoria |
| author_sort | Marzia Di Donato |
| collection | DOAJ |
| description | Abstract Malignant melanoma represents the fifth most common cancer in the world and its incidence is rising. Novel therapies targeting receptor tyrosine kinases, kinases and immune checkpoints have been employed with a significant improvement of the overall survival and long-term disease containment. Nevertheless, the disease often progresses and becomes resistant to the therapies. As such, the discovery of new targets and drugs for advanced melanoma still remains a difficult task. Gender disparities, with a female advantage in melanoma incidence and outcome, have been reported. Although emerging studies support the pro-tumorigenic role of androgen/androgen receptor axis in melanoma, the molecular bases of such evidence are still under intense investigation. We now report that ligand activation of the androgen receptor drives melanoma invasiveness and its escape from natural killer-mediated cytotoxic effect. By combining different experimental approaches, we observe that melanoma escape is mediated by the androgen-triggered shedding of the surface molecule MICA. Specific blockade of ADAM10 or androgen receptor impairs the androgen-induced MICA shedding and melanoma immune-escape. Further, the increase in MICA serum levels correlates with a poor outcome in melanoma patients treated with the anti-PD-1 monoclonal antibody, pembrolizumab. At last, melanoma cells depleted of the androgen receptor become more responsive to the most commonly used immunocheckpoint inhibitors, suggesting that the receptor dampens the immunotherapy efficacy. Taken together, our findings identify the androgen receptor as a diagnostic guidance in melanoma and support the repositioning of AR blockers in clinical management of patients. |
| format | Article |
| id | doaj-art-bcd6e0ca5c01419685c5032737c8c9e6 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-bcd6e0ca5c01419685c5032737c8c9e62025-01-26T12:54:49ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111710.1038/s41419-025-07350-4Role of the androgen receptor in melanoma aggressivenessMarzia Di Donato0Costanza Maria Cristiani1Mariaelena Capone2Cinzia Garofalo3Gabriele Madonna4Lucia Carmela Passacatini5Margaret Ottaviano6Paolo Antonio Ascierto7Ferdinando Auricchio8Ennio Carbone9Antimo Migliaccio10Gabriella Castoria11Department of Precision Medicine, University of Campania ‘L. Vanvitelli’- Via L. De Crecchio 7Neuroscience Research Center, Department of Medical and Surgical Sciences - ‘Magna Graecia’ University of CatanzaroDepartment of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS- Fondazione “G. Pascale”Department of Experimental and Clinical Medicine, ‘Magna Graecia’ University of CatanzaroDepartment of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS- Fondazione “G. Pascale”Physiology and Pharmacology of Pain, IRCCS San Raffaele RomaDepartment of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS- Fondazione “G. Pascale”Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS- Fondazione “G. Pascale”Department of Precision Medicine, University of Campania ‘L. Vanvitelli’- Via L. De Crecchio 7Department of Precision Medicine, University of Campania ‘L. Vanvitelli’- Via L. De Crecchio 7Department of Precision Medicine, University of Campania ‘L. Vanvitelli’- Via L. De Crecchio 7Department of Precision Medicine, University of Campania ‘L. Vanvitelli’- Via L. De Crecchio 7Abstract Malignant melanoma represents the fifth most common cancer in the world and its incidence is rising. Novel therapies targeting receptor tyrosine kinases, kinases and immune checkpoints have been employed with a significant improvement of the overall survival and long-term disease containment. Nevertheless, the disease often progresses and becomes resistant to the therapies. As such, the discovery of new targets and drugs for advanced melanoma still remains a difficult task. Gender disparities, with a female advantage in melanoma incidence and outcome, have been reported. Although emerging studies support the pro-tumorigenic role of androgen/androgen receptor axis in melanoma, the molecular bases of such evidence are still under intense investigation. We now report that ligand activation of the androgen receptor drives melanoma invasiveness and its escape from natural killer-mediated cytotoxic effect. By combining different experimental approaches, we observe that melanoma escape is mediated by the androgen-triggered shedding of the surface molecule MICA. Specific blockade of ADAM10 or androgen receptor impairs the androgen-induced MICA shedding and melanoma immune-escape. Further, the increase in MICA serum levels correlates with a poor outcome in melanoma patients treated with the anti-PD-1 monoclonal antibody, pembrolizumab. At last, melanoma cells depleted of the androgen receptor become more responsive to the most commonly used immunocheckpoint inhibitors, suggesting that the receptor dampens the immunotherapy efficacy. Taken together, our findings identify the androgen receptor as a diagnostic guidance in melanoma and support the repositioning of AR blockers in clinical management of patients.https://doi.org/10.1038/s41419-025-07350-4 |
| spellingShingle | Marzia Di Donato Costanza Maria Cristiani Mariaelena Capone Cinzia Garofalo Gabriele Madonna Lucia Carmela Passacatini Margaret Ottaviano Paolo Antonio Ascierto Ferdinando Auricchio Ennio Carbone Antimo Migliaccio Gabriella Castoria Role of the androgen receptor in melanoma aggressiveness Cell Death and Disease |
| title | Role of the androgen receptor in melanoma aggressiveness |
| title_full | Role of the androgen receptor in melanoma aggressiveness |
| title_fullStr | Role of the androgen receptor in melanoma aggressiveness |
| title_full_unstemmed | Role of the androgen receptor in melanoma aggressiveness |
| title_short | Role of the androgen receptor in melanoma aggressiveness |
| title_sort | role of the androgen receptor in melanoma aggressiveness |
| url | https://doi.org/10.1038/s41419-025-07350-4 |
| work_keys_str_mv | AT marziadidonato roleoftheandrogenreceptorinmelanomaaggressiveness AT costanzamariacristiani roleoftheandrogenreceptorinmelanomaaggressiveness AT mariaelenacapone roleoftheandrogenreceptorinmelanomaaggressiveness AT cinziagarofalo roleoftheandrogenreceptorinmelanomaaggressiveness AT gabrielemadonna roleoftheandrogenreceptorinmelanomaaggressiveness AT luciacarmelapassacatini roleoftheandrogenreceptorinmelanomaaggressiveness AT margaretottaviano roleoftheandrogenreceptorinmelanomaaggressiveness AT paoloantonioascierto roleoftheandrogenreceptorinmelanomaaggressiveness AT ferdinandoauricchio roleoftheandrogenreceptorinmelanomaaggressiveness AT enniocarbone roleoftheandrogenreceptorinmelanomaaggressiveness AT antimomigliaccio roleoftheandrogenreceptorinmelanomaaggressiveness AT gabriellacastoria roleoftheandrogenreceptorinmelanomaaggressiveness |