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Research Articles

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. Glitza, Jeffrey 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 and Michael A. Davies
Grant M. Fischer
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Ali Jalali
4Department of Neurosurgery, Baylor College of Medicine, Houston, Texas.
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David A. Kircher
5Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah.
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Won-Chul Lee
6Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • ORCID record for Won-Chul Lee
Jennifer L. McQuade
2Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • ORCID record for Jennifer L. McQuade
Lauren E. Haydu
7Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Aron Y. Joon
8Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Alexandre Reuben
9Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Mariana P. de Macedo
10Department of Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil.
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Fernando C. L. Carapeto
3Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Chendong Yang
11Children's Medical Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Anuj Srivastava
12Department of Computational Sciences, The Jackson Lab for Genomic Medicine, Farmington, Connecticut.
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Chandrashekar R. Ambati
13Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas.
14Advanced Technology Core, Alkek Center for Molecular Discovery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
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Arun Sreekumar
13Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas.
14Advanced Technology Core, Alkek Center for Molecular Discovery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
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Courtney W. Hudgens
3Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Barbara Knighton
2Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Wanleng Deng
2Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Sherise D. Ferguson
15Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Hussein A. Tawbi
2Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Isabella C. Glitza
2Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jeffrey E. Gershenwald
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Y. N. Vashisht Gopal
2Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Patrick Hwu
2Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jason T. Huse
3Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
16Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jennifer A. Wargo
6Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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P. Andrew Futreal
6Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Nagireddy Putluri
13Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas.
14Advanced Technology Core, Alkek Center for Molecular Discovery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
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Alexander J. Lazar
3Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
16Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Ralph J. DeBerardinis
11Children's Medical Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
17Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Joseph R. Marszalek
18Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jianjun Zhang
6Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Sheri L. Holmen
5Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah.
19Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah.
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Michael T. Tetzlaff
3Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
16Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Michael A. Davies
2Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
20Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: mdavies@mdanderson.org
DOI: 10.1158/2159-8290.CD-18-1489
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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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received December 20, 2018.
  • Revision received February 8, 2019.
  • Accepted February 12, 2019.
  • Published first February 20, 2019.
  • ©2019 American Association for Cancer Research.
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This OnlineFirst version was published on April 4, 2019
doi: 10.1158/2159-8290.CD-18-1489

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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. Glitza, Jeffrey 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 and Michael A. Davies
Cancer Discov April 4 2019 DOI: 10.1158/2159-8290.CD-18-1489

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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. Glitza, Jeffrey 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 and Michael A. Davies
Cancer Discov April 4 2019 DOI: 10.1158/2159-8290.CD-18-1489
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