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Sci Rep. 2017 Nov 15;7(1):15593. doi: 10.1038/s41598-017-15849-w.

5-Aminolevulinic Acid Guided Sampling of Glioblastoma Microenvironments Identifies Pro-Survival Signaling at Infiltrative Margins.

Author information

1
Departments of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, Georgia.
2
Pediatrics, Emory University, Atlanta, GA 30322, Georgia.
3
Emory University Graduate Program in Cancer Biology, Atlanta, GA 30322, Georgia.
4
Biomedical Informatics, Emory University, Atlanta, GA 30322, Georgia.
5
Winship Cancer Institute, Emory University, Atlanta, GA 30322, Georgia.
6
Emory University School of Medicine, Emory University, Atlanta, GA 30322, Georgia.
7
Biomedical Engineering, Emory University/Georgia Institute of Technology, Atlanta, GA 30322, Georgia.
8
Neurology, Emory University, Atlanta, GA 30322, Georgia.
9
Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, 10003, USA.
10
Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, 10003, USA. Constantinos.Hadjipanayis@mountsinai.org.
11
Departments of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, Georgia. dbrat@emory.edu.
12
Biomedical Informatics, Emory University, Atlanta, GA 30322, Georgia. dbrat@emory.edu.
13
Winship Cancer Institute, Emory University, Atlanta, GA 30322, Georgia. dbrat@emory.edu.
14
Emory University School of Medicine, Emory University, Atlanta, GA 30322, Georgia. dbrat@emory.edu.

Abstract

Glioblastoma (GBM) contains diverse microenvironments with uneven distributions of oncogenic alterations and signaling networks. The diffusely infiltrative properties of GBM result in residual tumor at neurosurgical resection margins, representing the source of relapse in nearly all cases and suggesting that therapeutic efforts should be focused there. To identify signaling networks and potential druggable targets across tumor microenvironments (TMEs), we utilized 5-ALA fluorescence-guided neurosurgical resection and sampling, followed by proteomic analysis of specific TMEs. Reverse phase protein array (RPPA) was performed on 205 proteins isolated from the tumor margin, tumor bulk, and perinecrotic regions of 13 previously untreated, clinically-annotated and genetically-defined high grade gliomas. Differential protein and pathway signatures were established and then validated using western blotting, immunohistochemistry, and comparable TCGA RPPA datasets. We identified 37 proteins differentially expressed across high-grade glioma TMEs. We demonstrate that tumor margins were characterized by pro-survival and anti-apoptotic proteins, whereas perinecrotic regions were enriched for pro-coagulant and DNA damage response proteins. In both our patient cohort and TCGA cases, the data suggest that TMEs possess distinct protein expression profiles that are biologically and therapeutically relevant.

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