Sarina K Mueller1,2,3, Angela L Nocera1,2, Simon T Dillon2,4,5,6, Xuesong Gu2,4,5,6, Olaf Wendler3, Hasan H Otu7, Towia A Libermann2,4,5,6, Benjamin S Bleier1,2. 1. Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA. 2. Harvard Medical School, Boston, MA. 3. Department of Otorhinolaryngology, Head and Neck Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. 4. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA. 5. Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Boston, MA. 6. Genomics, Proteomics, Bioinformatics and Systems Biology Center Beth Israel Deaconess Medical Center, Boston, MA. 7. Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Lincoln, NE.
Abstract
BACKGROUND: Exosomes are secreted epithelial-derived vesicles that contain a conserved protein array representative of their parent cell. Exosomes may be reproducibly and noninvasively purified from nasal mucus. The exosomal proteome can be quantified using SOMAscanTM , a highly multiplexed, aptamer-based proteomic platform. The purpose of this study was to determine whether chronic rhinosinusitis with nasal polyps (CRSwNP) has a unique predictive exosomal proteomic biosignature. METHODS: Exosomes were isolated from whole mucus sampled from control and CRSwNP patients (n = 20 per group) by differential ultracentrifugation. The SOMAscanTM platform was used to simultaneously quantify 1310 biologically relevant human proteins. Matched tissue and whole mucus proteomes were also analyzed. Differential protein expression and discriminatory power were calculated using the unweighted pair group method with arithmetic-mean and principal component analysis, respectively. Bioinformatic analysis was performed using Ingenuity Pathway, MetaCore, and GeneMANIA analyses. RESULTS: The exosomal proteome demonstrated 123 significantly (p < 0.05) differentially regulated proteins in CRSwNP relative to control. Eighty of these proteins overlapped with the matched CRSwNP tissue proteome as compared with only 4 among matched whole mucus samples. Forty-three significantly dysregulated pathway networks overlapped between the exosomal and tissue proteome in CRSwNP as compared with only 3 among matched whole mucus samples. The best-performing protein set (cystatin-SN, peroxiredoxin-5, and glycoprotein VI) achieved an area under the curve (AUC) value of up to 99%. CONCLUSION: Our data contribute a significant advance in the development of a reproducible, noninvasive, serial, and quantitative "liquid biopsy" for rhinosinusitis. The exosomal proteomic approach has revealed a unique biosignature associated with CRSwNP, which outperforms whole mucus sampling, and thus provides a method of noninvasive disease detection and proposes new potential therapeutic targets.
BACKGROUND: Exosomes are secreted epithelial-derived vesicles that contain a conserved protein array representative of their parent cell. Exosomes may be reproducibly and noninvasively purified from nasal mucus. The exosomal proteome can be quantified using SOMAscanTM , a highly multiplexed, aptamer-based proteomic platform. The purpose of this study was to determine whether chronic rhinosinusitis with nasal polyps (CRSwNP) has a unique predictive exosomal proteomic biosignature. METHODS: Exosomes were isolated from whole mucus sampled from control and CRSwNP patients (n = 20 per group) by differential ultracentrifugation. The SOMAscanTM platform was used to simultaneously quantify 1310 biologically relevant human proteins. Matched tissue and whole mucus proteomes were also analyzed. Differential protein expression and discriminatory power were calculated using the unweighted pair group method with arithmetic-mean and principal component analysis, respectively. Bioinformatic analysis was performed using Ingenuity Pathway, MetaCore, and GeneMANIA analyses. RESULTS: The exosomal proteome demonstrated 123 significantly (p < 0.05) differentially regulated proteins in CRSwNP relative to control. Eighty of these proteins overlapped with the matched CRSwNP tissue proteome as compared with only 4 among matched whole mucus samples. Forty-three significantly dysregulated pathway networks overlapped between the exosomal and tissue proteome in CRSwNP as compared with only 3 among matched whole mucus samples. The best-performing protein set (cystatin-SN, peroxiredoxin-5, and glycoprotein VI) achieved an area under the curve (AUC) value of up to 99%. CONCLUSION: Our data contribute a significant advance in the development of a reproducible, noninvasive, serial, and quantitative "liquid biopsy" for rhinosinusitis. The exosomal proteomic approach has revealed a unique biosignature associated with CRSwNP, which outperforms whole mucus sampling, and thus provides a method of noninvasive disease detection and proposes new potential therapeutic targets.
Authors: Conner J Massey; Fernando Diaz Del Valle; Waleed M Abuzeid; Joshua M Levy; Sarina Mueller; Corrina G Levine; Stephanie S Smith; Benjamin S Bleier; Vijay R Ramakrishnan Journal: Int Forum Allergy Rhinol Date: 2019-12-17 Impact factor: 3.858
Authors: Angela L Nocera; Sarina K Mueller; Alan D Workman; Dawei Wu; Kristen McDonnell; Peter M Sadow; Mansoor M Amiji; Benjamin S Bleier Journal: J Allergy Clin Immunol Date: 2022-05-31 Impact factor: 14.290
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Authors: Gautam N Shenoy; Maulasri Bhatta; Jenni L Loyall; Raymond J Kelleher; Joel M Bernstein; Richard B Bankert Journal: Immunol Invest Date: 2020-04-17 Impact factor: 3.657
Authors: William Yakah; Pratibha Singh; Joanne Brown; Barbara Stoll; Doug Burrin; Muralidhar H Premkumar; Hasan H Otu; Xuesong Gu; Simon T Dillon; Towia A Libermann; Steven D Freedman; Camilia R Martin Journal: Am J Physiol Gastrointest Liver Physiol Date: 2020-11-25 Impact factor: 4.052
Authors: Katarzyna Piszczatowska; Katarzyna Czerwaty; Anna M Cyran; Mathias Fiedler; Nils Ludwig; Jacek Brzost; Mirosław J Szczepański Journal: Diagnostics (Basel) Date: 2021-02-02