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Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases

There is a critical need to improve our understanding of the pathogenesis of -melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival. Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U-13C]-glucose tracing in vivo IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor-resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001005046 Illumina HiSeq 2000 Illumina MiSeq 199
Publications Citations
Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases.
Cancer Discov 9: 2019 628-645
144
Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition.
Cancer Discov 10: 2020 1352-1373
98
Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis.
Cancer Discov 12: 2022 1314-1335
25
Decoding molecular programs in melanoma brain metastases.
Nat Commun 13: 2022 7304
3
Type I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment.
Nat Commun 14: 2023 2632
1