Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Cancer discovery, 2019-05, Vol.9 (5), p.628-645

Ort / Verlag

United States

Erscheinungsjahr

2019

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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- C]-glucose tracing . 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. . .