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In-depth patient-specific analysis of tumor heterogeneity in melanoma brain metastasis : Insights from spatial transcriptomics and multi-region bulk sequencing

Sharma, Nidhi ; Rájová, Jana LU ; Mermelekas, Georgios ; Thrane, Kim ; Lundeberg, Joakim ; Shamikh, Alia ; Vikström, Sofi ; Babačić, Haris ; Jensdottir, Margret and Lehtiö, Janne , et al. (2025) In Translational Oncology 59.
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Immune signaling, Immunotherapy, Melanoma brain metastases, Multiomics, PD-1, Proteomics, Targeted therapy, Transcriptomics
in
Translational Oncology
volume
59
article number
102468
publisher
Neoplasia Press
external identifiers
  • pmid:40669378
  • scopus:105010601570
ISSN
1936-5233
DOI
10.1016/j.tranon.2025.102468
language
English
LU publication?
yes
id
4db515d6-8838-4142-8a23-406e6bb20058
date added to LUP
2025-11-05 13:23:28
date last changed
2025-12-17 17:32:53
@article{4db515d6-8838-4142-8a23-406e6bb20058,
  abstract     = {{<p>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.</p>}},
  author       = {{Sharma, Nidhi and Rájová, Jana and Mermelekas, Georgios and Thrane, Kim and Lundeberg, Joakim and Shamikh, Alia and Vikström, Sofi and Babačić, Haris and Jensdottir, Margret and Lehtiö, Janne and Pernemalm, Maria and Eriksson, Hanna}},
  issn         = {{1936-5233}},
  keywords     = {{Immune signaling; Immunotherapy; Melanoma brain metastases; Multiomics; PD-1; Proteomics; Targeted therapy; Transcriptomics}},
  language     = {{eng}},
  publisher    = {{Neoplasia Press}},
  series       = {{Translational Oncology}},
  title        = {{In-depth patient-specific analysis of tumor heterogeneity in melanoma brain metastasis : Insights from spatial transcriptomics and multi-region bulk sequencing}},
  url          = {{http://dx.doi.org/10.1016/j.tranon.2025.102468}},
  doi          = {{10.1016/j.tranon.2025.102468}},
  volume       = {{59}},
  year         = {{2025}},
}