In-depth patient-specific analysis of tumor heterogeneity in melanoma brain metastasis: Insights from spatial transcriptomics and multi-region bulk sequencing.
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Sharma N, Rájová J, Mermelekas G, Thrane K, Lundeberg J, Shamikh A, Vikström S, Babačić H, Jensdottir M, Lehtiö J, Pernemalm M, Eriksson H
Transl Oncol 59 (-) 102468 [2025-07-15; online 2025-07-15]
Melanoma brain metastases (MBM) exhibit extensive intertumor and intratumor heterogeneity (ITH), driven by a complex tumor microenvironment. The aim of this study was to perform a detailed analysis of individual MBM patient tumors using a multiomics approach, integrating spatial transcriptomics with multi-region bulk exome, proteome, and transcriptome profiling for a small group of four patient samples. We identified significant patient-specific variations in immune cell infiltration, particularly in B/plasma cells, myeloid cells, and cancer-associated fibroblasts (CAFs). Notably, immunotherapy-treated patients showed enriched pathways related to epithelial-mesenchymal transition (EMT), interferon-gamma (IFN-γ) signaling, oxidative phosphorylation, T-cell signaling, inflammation and DNA damage, which aligned with distinct cellular compositions observed in the spatial analysis. We also uncovered considerable ITH, especially at the protein level, revealing differential expression patterns of key tumor and immune-related markers. The correlation between mRNA and protein data highlighted consistent enrichment of critical pathways across multiomics layers. These findings highlight the molecular and cellular landscape of individual patient MBM, underscoring the importance of addressing tumor heterogeneity in the development of effective therapeutic strategies.
NGI Stockholm (Genomics Production) [Service]
National Genomics Infrastructure [Service]
PubMed 40669378
DOI 10.1016/j.tranon.2025.102468
Crossref 10.1016/j.tranon.2025.102468
pii: S1936-5233(25)00199-8