GPNMB marks a quiescent cell population in melanoma and promotes metastasis formation
Melanoma exhibits high intratumoral heterogeneity, characterized by a diverse population of cells undergoing dynamic transitions between cellular states. These adaptive changes enable melanoma cells to survive in the harsh tumor microenvironment, acquire drug resistance, and metastasize. One such state, quiescence, has been linked to both relapse and drug resistance, but its underlying biology and molecular mechanisms remain poorly understood. Our study challenges the conventional understanding of melanoma quiescence. Contrary to the notion of a rare, unique subpopulation, we demonstrate that quiescence is a highly dynamic state accessible to most, if not all, melanoma cells. This state is exquisitely sensitive to microenvironmental cues. We identify GPNMB as a marker of quiescence, that is expressed in both primary and metastatic tumors. GPNMB-positive cells exhibit a pro-metastatic phenotype and are enriched in metastatic sites, suggesting a potential role for quiescence in tumor dissemination. Our findings position GPNMB as a valuable marker for isolating quiescent melanoma cells and as a potential therapeutic target to tackle metastasis.
Authors
- Federica Marocchi (ORCID: https://orcid.org/0000-0002-5610-5499)
- Daniela Bossi (ORCID: https://orcid.org/0000-0002-8507-6754)
- Pier Francesco Ferrucci (ORCID: https://orcid.org/0000-0001-6255-5851)
- Lucilla Luzi (ORCID: https://orcid.org/0000-0002-8746-4179)
- Massimo Barberis (ORCID: https://orcid.org/0000-0002-0943-4804)
- Luisa Lanfrancone (ORCID: https://orcid.org/0000-0002-4523-3815)
- Marco S. Nobile (ORCID: https://orcid.org/0000-0002-7692-7203)
- Chiara Soriani (ORCID: https://orcid.org/0000-0003-4363-6597)
- Pier Giuseppe Pelicci (ORCID: https://orcid.org/0000-0002-5076-2316)
- Barbara Gallo (ORCID: https://orcid.org/0000-0001-8567-9259)
- Marco Malferrari (ORCID: https://orcid.org/0000-0003-1613-1593)
- Stefania Rapino (ORCID: https://orcid.org/0000-0001-6913-0119)
- Marina Melixetian (ORCID: https://orcid.org/0000-0002-8454-8262)
- Thalia Vlachou (ORCID: https://orcid.org/0000-0001-5264-3591)
- Fiorenza Lotti (ORCID: https://orcid.org/0000-0003-4897-0420)
- Leone Bacciu (ORCID: https://orcid.org/0009-0006-2175-8779)
- Ilaria Ferrarotto
- Nicolò Quaresima
- Velia Mollo
Institutions
- Ca' Foscari University of Venice (IT)
- University of Milan (IT)
- MultiMedica (IT)
- Institute of Oncology Research (CH)
- Frontier Science Foundation-Hellas (GR)
- European Institute of Oncology (IT)
- University of Bologna (IT)
Publication Details
- Journal
- EMBO Reports
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1038/s44319-025-00501-w
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministero della Salute
- Fondazione Umberto Veronesi
- Associazione Italiana per la Ricerca sul Cancro