Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Fischer Grant M, Jalali Ali, Kircher David A, Lee Won-Chul, McQuade Jennifer L, Haydu Lauren E, Joon Aron Y, Reuben Alexandre, de Macedo Mariana P, Carapeto Fernando C L, Yang Chendong, Srivastava Anuj, Ambati Chandrashekar R, Sreekumar Arun, Hudgens Courtney W, Knighton Barbara, Deng Wanleng, Ferguson Sherise D, Tawbi Hussein A, Glitza Isabella C, Gershenwald Jeffrey E, Vashisht Gopal Y N, Hwu Patrick, Huse Jason T, Wargo Jennifer A, Futreal P Andrew, Putluri Nagireddy, Lazar Alexander J, DeBerardinis Ralph J, Marszalek Joseph R, Zhang Jianjun, Holmen Sheri L, Tetzlaff Michael T, Davies Michael A
Аннотация
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.