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

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.

SUBMITTER: Fischer GM

PROVIDER: S-EPMC6497554 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Fischer Grant M GM Jalali Ali A Kircher David A DA Lee Won-Chul WC McQuade Jennifer L JL Haydu Lauren E LE Joon Aron Y AY Reuben Alexandre A de Macedo Mariana P MP Carapeto Fernando C L FCL Yang Chendong C Srivastava Anuj A Ambati Chandrashekar R CR Sreekumar Arun A Hudgens Courtney W CW Knighton Barbara B Deng Wanleng W Ferguson Sherise D SD Tawbi Hussein A HA Glitza Isabella C IC Gershenwald Jeffrey E JE Vashisht Gopal Y N YN Hwu Patrick P Huse Jason T JT Wargo Jennifer A JA Futreal P Andrew PA Putluri Nagireddy N Lazar Alexander J AJ DeBerardinis Ralph J RJ Marszalek Joseph R JR Zhang Jianjun J Holmen Sheri L SL Tetzlaff Michael T MT Davies Michael A MA

Cancer discovery 20190220 5

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 ident ...[more]

PMID: 30787016

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Project description:There is an urgent need to improve our understanding of breast cancer brain metastases (BCBMs). Thus, we obtained transcriptome data of BCBMs, primary breast cancers (BCs), and extracranial metastases (BCEMs) from the Gene Expression Omnibus (GEO) database, including GSE43837, GSE14017, and GSE14018, for immune and metabolic analysis. Firstly, we performed immune and metabolic analysis on BCBMs and primary breast cancers of GSE43837 using RNA sequence. We identified significant immunosuppression and gene signatures associated with immune infiltration in BCBMs; the lower the expression of the signatures, the worse the prognosis of breast cancer patients in the Kaplan-Meier (KM) plotter [Breast cancer] database. We also identified increased oxidative phosphorylation (OXPHOS) utilization in BCBMs compared with BCs and gene signatures associated with increased OXPHOS utilization in BCBMs; the higher the expression of the signatures, the worse the prognosis of breast cancer patients in the KM plotter [Breast cancer] database, which can predict the prognosis of breast cancer patients better, as it can also predict the prognosis of patients with different breast cancer subtypes. In addition, we performed immune and metabolic analysis on BCBMs and extracranial metastases of GSE14017 and GSE14018 using RNA sequence. Compared with extracranial metastases, we identified more significant immunosuppression but no difference in OXPHOS utilization in BCBMs, which may be because OXPHOS was also involved in extracranial metastases. We have proven that OXPHOS was functionally significant in metastasis in vitro assays. Oligomycin, an OXPHOS inhibitor, substantially attenuated the migration and invasion potential of breast cancer cells. Our study provides new insights into the pathogenesis of BCBMs.SignificanceOur study reports the most comprehensive gene expression analysis of BCBMs, BCs and extracranial metastases to date. We identified immunosuppression and OXPHOS enrichment in BCBMs compared with BCs, which provide new insights into the pathogenesis of BCBMs and will facilitate the development of new therapeutic strategies for patients with BCBMs.

Dataset Information

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

Publications

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

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