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Cancer Discov. 2019 May;9(5):628-645. doi: 10.1158/2159-8290.CD-18-1489. Epub 2019 Feb 20.

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

Author information

1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Neurosurgery, Baylor College of Medicine, Houston, Texas.
5
Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah.
6
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Department of Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil.
11
Children's Medical Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
12
Department of Computational Sciences, The Jackson Lab for Genomic Medicine, Farmington, Connecticut.
13
Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas.
14
Advanced Technology Core, Alkek Center for Molecular Discovery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
15
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
16
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
17
Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
18
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
19
Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah.
20
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. mdavies@mdanderson.org.
21
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Abstract

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. SIGNIFICANCE: Improving our understanding of the pathogenesis of MBMs will facilitate the rational development and prioritization of new therapeutic strategies. This study reports the most comprehensive molecular profiling of patient-matched MBMs and extracranial metastases to date. The data provide new insights into MBM biology and therapeutic resistance.See related commentary by Egelston and Margolin, p. 581.This article is highlighted in the In This Issue feature, p. 565.

PMID:
30787016
PMCID:
PMC6497554
[Available on 2019-11-01]
DOI:
10.1158/2159-8290.CD-18-1489

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