Samples & cell type composition in sc/snRNA-seq.
<div><p>Melanoma brain metastasis (MBM) remains lethal with limited treatment efficacy. Meanwhile, the cellular origins and drivers of brain metastasis from melanoma have yet to be defined. Through integrated single-cell/single-nucleus RNA sequencing of 26 melanoma samples, we identified...
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2025
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| Riassunto: | <div><p>Melanoma brain metastasis (MBM) remains lethal with limited treatment efficacy. Meanwhile, the cellular origins and drivers of brain metastasis from melanoma have yet to be defined. Through integrated single-cell/single-nucleus RNA sequencing of 26 melanoma samples, we identified a pre-brain-metastatic tumor subpopulation (MBMATCs, MBM-associated tumor cells) within a conserved malignant cell trajectory (Mela3). MBMATCs exhibited activated pro-metastatic pathways and upregulated neural/adhesion genes (<i>NRG3</i>, <i>NCAM1</i>), suggesting a cellular origin for brain tropism. MBM ecosystems showed T cell exhaustion (elevated <i>PD-1</i>, <i>HAVCR2</i>, <i>LAG3</i>) and Treg enrichment. An MBM-Index derived from bulk RNA-seq accurately quantifies MBMATCs abundance, independently predicting poor overall survival in both TCGA-SKCM and validation cohorts. Furthermore, we assessed the clinical relevance of the MBM-Index and uncovered five candidate drugs with potential activity against MBMATCs. This study identifies MBMATCs as brain metastasis associated tumor cells and positions the MBM-Index as a biomarker for early stratification of melanoma patients at high risk of brain metastasis.</p></div> |
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