Lotti Fiorenza, Melixetian Marine, Vlachou Thalia, Nobile Marco S, Bacciu Leone, Malferrari Marco, Quaresima Nicolò, Rapino Stefania, Marocchi Federica, Barberis Massimo, Soriani Chiara, Gallo Barbara, Mollo Velia, Ferrarotto Ilaria, Bossi Daniela, Ferrucci Pier Francesco, Pelicci Pier Giuseppe, Luzi Lucilla, Lanfrancone Luisa
Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy.
Purposeful, Tritis Septembriou 144, Athens, 11251, Greece.
EMBO Rep. 2025 Jun 17. doi: 10.1038/s44319-025-00501-w.
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.
黑色素瘤表现出高度的肿瘤内异质性,其特征是一群多样化的细胞在不同细胞状态之间进行动态转变。这些适应性变化使黑色素瘤细胞能够在恶劣的肿瘤微环境中存活、获得耐药性并发生转移。其中一种状态,即静止状态,已被证明与复发和耐药性都有关联,但其潜在的生物学特性和分子机制仍知之甚少。我们的研究对黑色素瘤静止状态的传统理解提出了挑战。与罕见、独特亚群的概念相反,我们证明静止状态是一种高度动态的状态,大多数(如果不是所有)黑色素瘤细胞都能进入这种状态。这种状态对微环境线索极为敏感。我们确定糖蛋白非metastatic黑色素瘤蛋白B(GPNMB)为静止状态的标志物,它在原发性和转移性肿瘤中均有表达。GPNMB阳性细胞表现出促转移表型,且在转移部位富集,这表明静止状态在肿瘤播散中可能发挥作用。我们的研究结果将GPNMB定位为分离静止黑色素瘤细胞的有价值标志物以及应对转移的潜在治疗靶点。
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