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

• Type of Material: Article
• Authors: James L. Ross, Emory University; Lee Cooper, Emory University; Jun Kong, Emory University; David Gutman, Emory University; Merete Williams, Emory University; Carol Tucker-Burden, Emory University; Myles R. McCrary, Emory University; Alexandros Bouras, Icahn School of Medicine at Mount Sinai; Milota Kaluzova, Emory University; William D. Dunn, Emory University; Duc Duong, Emory University; Constantinos Hadjipanayis, Emory University; Daniel Brat, Emory University
• Language: English
• Date: 2017-11-15
• Publisher: Nature Publishing Group: Open Access Journals - Option C
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2017
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-017-15849-w
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 7
• Issue: 1
• Start Page: 15593
• End Page: 15593
• Grant/Funding Information: This work was supported by the U.S. Public Health Service through National Institutes of Health grants R01CA176659 (D.J. Brat; C.G. Hadjipanayis); U24CA194362 (D. Gutman/L. Cooper), K22LM011576 (L. Cooper), K25CA181503 (J. Kong); and the Winship Cancer Institute NCI Cancer Center Support Grant (P30CA138292).; The authors thank the Tissue Procurement Service and the Research Pathology Laboratory of the Cancer Tissue and Pathology Shared Resource, as well as the Proteomics Shared Resource at the Winship Cancer Institute, supported by the NCI Cancer Center Support Grant (P30CA138292).
• Research Categories: Biology, Neuroscience; Health Sciences, Oncology

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.