Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.
IF: 66.850
Cited by: 1


Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.


Spatial Transcriptomics
brain metastasis
chromosomal instability
neuronal-like cell state
single-cell genomics
spatial transcriptomics

MeSH terms

Brain Neoplasms
CD8-Positive T-Lymphocytes


Biermann, Jana
Melms, Johannes C
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Wang, Yiping
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Tagore, Somnath
Barrera, Irving
Ibarra-Arellano, Miguel A
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Mangipudy, Vaibhav S
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Wünnemann, Florian
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Rapisuwon, Suthee
Slingluff, Craig L Jr
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Röcken, Martin
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Agrawal, Praveen
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Macosko, Evan Z
Chen, Fei
Schwartz, Gary K
Izar, Benjamin