Molecular profiling reveals unique immune and metabolic features of melanoma brain metastases

Grant M. Fischer, Ali Jalali, David A. Kircher, Won Chul Lee, Jennifer L. McQuade, Lauren E. Haydu, Aron Y. Joon, Alexandre Reuben, Mariana P. de Macedo, Fernando C.L. Carapeto, Chendong Yang, Anuj Srivastava, Chandrashekar R. Ambati, Arun Sreekumar, Courtney W. Hudgens, Barbara Knighton, Wanleng Deng, Sherise D. Ferguson, Hussein A. Tawbi, Isabella C. GlitzaJeffrey E. Gershenwald, Y. N. Vashisht Gopal, Patrick Hwu, Jason T. Huse, Jennifer A. Wargo, P. Andrew Futreal, Nagireddy Putluri, Alexander J. Lazar, Ralph J. Deberardinis, Joseph R. Marszalek, Jianjun Zhang, Sheri L. Holmen, Michael T. Tetzlaff, Michael A. Davies

Research output: Contribution to journalArticle

21 Scopus citations

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 profi ling of patient-matched MBMs and extracranial metastases to date. The data provide new insights into MBM biology and therapeutic resistance.

Original languageEnglish (US)
Pages (from-to)628-645
Number of pages18
JournalCancer discovery
Volume9
Issue number5
DOIs
StatePublished - May 2019

    Fingerprint

ASJC Scopus subject areas

  • Oncology

Cite this

Fischer, G. M., Jalali, A., Kircher, D. A., Lee, W. C., McQuade, J. L., Haydu, L. E., Joon, A. Y., Reuben, A., de Macedo, M. P., Carapeto, F. C. L., Yang, C., Srivastava, A., Ambati, C. R., Sreekumar, A., Hudgens, C. W., Knighton, B., Deng, W., Ferguson, S. D., Tawbi, H. A., ... Davies, M. A. (2019). Molecular profiling reveals unique immune and metabolic features of melanoma brain metastases. Cancer discovery, 9(5), 628-645. https://doi.org/10.1158/2159-8290.CD-18-1489