Ewing sarcoma family of tumors-derived small extracellular vesicle proteomics identify potential clinical biomarkers
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Glenson Samuel1,2,3,*, Jennifer Crow4,*, Jon B. Klein5,6, Michael L. Merchant5, Emily Nissen7, Devin C. Koestler3,7, Kris Laurence1, Xiaobo Liang4, Kathleen Neville8, Vincent Staggs2,9, Atif Ahmed2,10, Safinur Atay4,11 and Andrew K. Godwin3,4
1 Division of Pediatric Hematology Oncology and Bone Marrow Transplantation, Children’s Mercy Hospital, Kansas City, MO, USA
2 Department of Pediatrics, University of Missouri-Kansas City, Kansas City, MO, USA
3 University of Kansas Cancer Center, Kansas City, KS, USA
4 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
5 Clinical Proteomics Laboratory, Department of Medicine, University of Louisville, Louisville, KY, USA
6 Robley Rex VA Medical Center, Louisville, KY, USA
7 Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS, USA
8 Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
9 Biostatistics & Epidemiology Core, Children’s Mercy Hospital, Kansas City, MO, USA
10 Department of Pathology, Children’s Mercy Hospital, Kansas City, MO, USA
11 Bristol-Myers Squibb, Cambridge, MA, USA
* These authors contributed equally to this work
|Andrew K. Godwin,||email:||[email protected]|
Keywords: Ewing sarcoma; EWS-ETS; biomarkers; extracellular vesicles; exosomes
Received: April 18, 2020 Accepted: June 20, 2020 Published: August 04, 2020
Purpose: Ewing Sarcoma Family of Tumors (ESFT), the second most common pediatric osseous malignancy, are characterized by the pathognomonic chromosomal EWS-ETS translocation. Outside of tumor biopsy, no clinically relevant ESFT biomarkers exist. Additionally, tumor burden assessment at diagnosis, monitoring of disease responsiveness to therapy, and detection of disease recurrence are limited to radiographic imaging. To identify new, clinically relevant biomarkers we evaluated the proteome of a subset of ESFT-derived small extracellular vesicles (sEVs).
Materials and Methods: We performed the first high quality proteomic study of ESFT-derived sEVs from 5 ESFT cell lines representing the most common EWS-ETS fusion types and identified 619 proteins composing the core ESFT sEV proteome. We compared these core proteins to databases of common plasma-based proteins and sEV-associated proteins found within healthy plasma to identify proteins unique or enriched within ESFT.
Results: From these analyses, two membrane bound proteins with biomarker potential were selected, CD99/MIC2 and NGFR, to develop a liquid-based assay enriching of ESFT-associated sEVs and detection of sEV mRNA cargo (i.e., EWS-ETS transcripts). We employed this immuno-enrichment approach to diagnosis of ESFT utilizing plasma (250 μl) from both localized and metastatic ESFT pediatric patients and cancer-free controls, and showed significant diagnostic power [AUC = 0.92, p = 0.001 for sEV numeration, with a PPV = 1.00, 95% CI = (0.63, 1.00) and a NPV = 0.67, 95% CI = (0.30, 0.93)].
Conclusions: In this study, we demonstrate utilization of circulating ESFT-associated sEVs in pediatric patients as a source of minimally invasive diagnostic and potentially prognostic biomarkers.
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