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Discovery of Spatial Peptide Signatures for Neuroblastoma Risk Assessment by MALDI Mass Spectrometry Imaging

BIH Center for Regenerative Therapies BCRT, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
Department of Pediatric Oncology, Helios Klinikum Berlin-Buch, 13125 Berlin, Germany
Department of Pediatric Oncology & Hematology, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
Partner Site Berlin, The German Cancer Consortium (DKTK), 10117 Berlin, Germany
The German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
Institute of Pathology, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany
Berlin Institute of Health, Charité—Universitätsmedizin Berlin (BIH), 10178 Berlin, Germany
Author to whom correspondence should be addressed.
Academic Editors: Fabio Pagni, Stefania Galimberti and Maria Valeria Corrias
Cancers 2021, 13(13), 3184;
Received: 23 April 2021 / Revised: 16 June 2021 / Accepted: 22 June 2021 / Published: 25 June 2021
The childhood tumor, neuroblastoma, has a broad clinical presentation. Risk assessment at diagnosis is particularly difficult in molecularly heterogeneous high-risk cases. Here we investigate the potential of imaging mass spectrometry to directly detect intratumor heterogeneity on the protein level in tissue sections. We show that this approach can produce discriminatory peptide signatures separating high- from low- and intermediate-risk tumors, identify 8 proteins aassociated with these signatures and validate two marker proteins using tissue immunostaining that have promise for further basic and translational research in neuroblastoma. We provide proof-of-concept that mass spectrometry-based technology could assist early risk assessment in neuroblastoma and provide insights into peptide signature-based detection of intratumor heterogeneity.
Risk classification plays a crucial role in clinical management and therapy decisions in children with neuroblastoma. Risk assessment is currently based on patient criteria and molecular factors in single tumor biopsies at diagnosis. Growing evidence of extensive neuroblastoma intratumor heterogeneity drives the need for novel diagnostics to assess molecular profiles more comprehensively in spatial resolution to better predict risk for tumor progression and therapy resistance. We present a pilot study investigating the feasibility and potential of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to identify spatial peptide heterogeneity in neuroblastoma tissues of divergent current risk classification: high versus low/intermediate risk. Univariate (receiver operating characteristic analysis) and multivariate (segmentation, principal component analysis) statistical strategies identified spatially discriminative risk-associated MALDI-based peptide signatures. The AHNAK nucleoprotein and collapsin response mediator protein 1 (CRMP1) were identified as proteins associated with these peptide signatures, and their differential expression in the neuroblastomas of divergent risk was immunohistochemically validated. This proof-of-concept study demonstrates that MALDI-MSI combined with univariate and multivariate analysis strategies can identify spatially discriminative risk-associated peptide signatures in neuroblastoma tissues. These results suggest a promising new analytical strategy improving risk classification and providing new biological insights into neuroblastoma intratumor heterogeneity. View Full-Text
Keywords: neuroblastoma; risk assessment; intratumor heterogeneity; peptide signatures; MALDI-MSI neuroblastoma; risk assessment; intratumor heterogeneity; peptide signatures; MALDI-MSI
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MDPI and ACS Style

Wu, Z.; Hundsdoerfer, P.; Schulte, J.H.; Astrahantseff, K.; Boral, S.; Schmelz, K.; Eggert, A.; Klein, O. Discovery of Spatial Peptide Signatures for Neuroblastoma Risk Assessment by MALDI Mass Spectrometry Imaging. Cancers 2021, 13, 3184.

AMA Style

Wu Z, Hundsdoerfer P, Schulte JH, Astrahantseff K, Boral S, Schmelz K, Eggert A, Klein O. Discovery of Spatial Peptide Signatures for Neuroblastoma Risk Assessment by MALDI Mass Spectrometry Imaging. Cancers. 2021; 13(13):3184.

Chicago/Turabian Style

Wu, Zhiyang, Patrick Hundsdoerfer, Johannes H. Schulte, Kathy Astrahantseff, Senguel Boral, Karin Schmelz, Angelika Eggert, and Oliver Klein. 2021. "Discovery of Spatial Peptide Signatures for Neuroblastoma Risk Assessment by MALDI Mass Spectrometry Imaging" Cancers 13, no. 13: 3184.

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