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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.

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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
Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition.
Cancer Discov 10: 2020 1352-1373
Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis.
Cancer Discov 12: 2022 1314-1335
Decoding molecular programs in melanoma brain metastases.
Nat Commun 13: 2022 7304
Type I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment.
Nat Commun 14: 2023 2632