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

Grant M. Fischer(The University of Texas MD Anderson Cancer Center), Ali Jalali(Baylor College of Medicine), David A. Kircher(University of Utah), Won‐Chul Lee(The University of Texas MD Anderson Cancer Center), Jennifer L. McQuade(The University of Texas MD Anderson Cancer Center), Lauren E. Haydu(The University of Texas MD Anderson Cancer Center), Aron Y. Joon(The University of Texas MD Anderson Cancer Center), Alexandre Reuben(The University of Texas MD Anderson Cancer Center), Mariana Petaccia de Macêdo(AC Camargo Hospital), Fernando C. L. Carapeto(The University of Texas MD Anderson Cancer Center), Chendong Yang(The University of Texas Southwestern Medical Center), Anuj Srivastava(Jackson Laboratory), Chandrashekar R. Ambati(Baylor College of Medicine), Arun Sreekumar(Baylor College of Medicine), Courtney W. Hudgens(The University of Texas MD Anderson Cancer Center), Barbara Knighton(The University of Texas MD Anderson Cancer Center), Wanleng Deng(The University of Texas MD Anderson Cancer Center), Sherise D. Ferguson(The University of Texas MD Anderson Cancer Center), Hussein A. Tawbi(The University of Texas MD Anderson Cancer Center), Isabella C. Glitza(The University of Texas MD Anderson Cancer Center), Jeffrey E. Gershenwald(The University of Texas MD Anderson Cancer Center), Y.N. Vashisht Gopal(The University of Texas MD Anderson Cancer Center), Patrick Hwu(The University of Texas MD Anderson Cancer Center), Jason T. Huse(The University of Texas MD Anderson Cancer Center), Jennifer A. Wargo(The University of Texas MD Anderson Cancer Center), P. Andrew Futreal(The University of Texas MD Anderson Cancer Center), Nagireddy Putluri(Baylor College of Medicine), Alexander J. Lazar(The University of Texas MD Anderson Cancer Center), Ralph J. DeBerardinis(Howard Hughes Medical Institute), Joseph R. Marszalek(The University of Texas MD Anderson Cancer Center), Jianjun Zhang(The University of Texas MD Anderson Cancer Center), Sheri L. Holmen(University of Utah), Michael T. Tetzlaff(The University of Texas MD Anderson Cancer Center), Michael A. Davies(The University of Texas MD Anderson Cancer Center)
Cancer Discovery
February 20, 2019
10.1158/2159-8290.cd-18-1489
Cited by 346Open Access
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Abstract

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

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