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Ultrasensitive Immunoprofiling of Plasma Extracellular Vesicles Identifies Syndecan-1 as a Potential Tool for Minimally Invasive Diagnosis of Glioma

Indira Chandran, Vineesh LU ; Welinder, Charlotte LU ; Månsson, Ann-Sofie LU ; Offer, Svenja LU ; Freyhult, Eva ; Pernemalm, Maria ; Lund, Sigrid M ; Pedersen, Shona ; Lehtiö, Janne and Marko-Varga, Gyorgy LU , et al. (2019) In Clinical Cancer Research 25(10). p.3115-3127
Abstract

Purpose: Liquid biopsy has great potential to improve the management of brain tumor patients at high risk of surgery-associated complications. Here, the aim was to explore plasma extracellular vesicle (plEV) immunoprofiling as a tool for noninvasive diagnosis of glioma.Experimental Design: PlEV isolation and analysis were optimized using advanced mass spectrometry, nanoparticle tracking analysis, and electron microscopy. We then established a new procedure that combines size exclusion chromatography isolation and proximity extension assay-based ultrasensitive immunoprofiling of plEV proteins that was applied on a well-defined glioma study cohort (n = 82).Results: Among potential candidates, we for the first time identify syndecan-1... (More)

Purpose: Liquid biopsy has great potential to improve the management of brain tumor patients at high risk of surgery-associated complications. Here, the aim was to explore plasma extracellular vesicle (plEV) immunoprofiling as a tool for noninvasive diagnosis of glioma.Experimental Design: PlEV isolation and analysis were optimized using advanced mass spectrometry, nanoparticle tracking analysis, and electron microscopy. We then established a new procedure that combines size exclusion chromatography isolation and proximity extension assay-based ultrasensitive immunoprofiling of plEV proteins that was applied on a well-defined glioma study cohort (n = 82).Results: Among potential candidates, we for the first time identify syndecan-1 (SDC1) as a plEV constituent that can discriminate between high-grade glioblastoma multiforme (GBM, WHO grade IV) and low-grade glioma [LGG, WHO grade II; area under the ROC curve (AUC): 0.81; sensitivity: 71%; specificity: 91%]. These findings were independently validated by ELISA. Tumor SDC1 mRNA expression similarly discriminated between GBM and LGG in an independent glioma patient population from The Cancer Genome Atlas cohort (AUC: 0.91; sensitivity: 79%; specificity: 91%). In experimental studies with GBM cells, we show that SDC1 is efficiently sorted to secreted EVs. Importantly, we found strong support of plEVSDC1 originating from GBM tumors, as plEVSDC1 correlated with SDC1 protein expression in matched patient tumors, and plEVSDC1 was decreased postoperatively depending on the extent of surgery.Conclusions: Our studies support the concept of circulating plEVs as a tool for noninvasive diagnosis and monitoring of gliomas and should move this field closer to the goal of improving the management of cancer patients.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
25
issue
10
pages
3115 - 3127
publisher
American Association for Cancer Research
external identifiers
  • pmid:30679164
  • scopus:85065785426
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-18-2946
language
English
LU publication?
yes
additional info
©2019 American Association for Cancer Research.
id
79d84a7e-2a38-4e9f-b6c4-5e22ca6e33be
date added to LUP
2019-05-22 08:55:57
date last changed
2024-06-26 16:39:23
@article{79d84a7e-2a38-4e9f-b6c4-5e22ca6e33be,
  abstract     = {{<p>Purpose: Liquid biopsy has great potential to improve the management of brain tumor patients at high risk of surgery-associated complications. Here, the aim was to explore plasma extracellular vesicle (plEV) immunoprofiling as a tool for noninvasive diagnosis of glioma.Experimental Design: PlEV isolation and analysis were optimized using advanced mass spectrometry, nanoparticle tracking analysis, and electron microscopy. We then established a new procedure that combines size exclusion chromatography isolation and proximity extension assay-based ultrasensitive immunoprofiling of plEV proteins that was applied on a well-defined glioma study cohort (n = 82).Results: Among potential candidates, we for the first time identify syndecan-1 (SDC1) as a plEV constituent that can discriminate between high-grade glioblastoma multiforme (GBM, WHO grade IV) and low-grade glioma [LGG, WHO grade II; area under the ROC curve (AUC): 0.81; sensitivity: 71%; specificity: 91%]. These findings were independently validated by ELISA. Tumor SDC1 mRNA expression similarly discriminated between GBM and LGG in an independent glioma patient population from The Cancer Genome Atlas cohort (AUC: 0.91; sensitivity: 79%; specificity: 91%). In experimental studies with GBM cells, we show that SDC1 is efficiently sorted to secreted EVs. Importantly, we found strong support of plEVSDC1 originating from GBM tumors, as plEVSDC1 correlated with SDC1 protein expression in matched patient tumors, and plEVSDC1 was decreased postoperatively depending on the extent of surgery.Conclusions: Our studies support the concept of circulating plEVs as a tool for noninvasive diagnosis and monitoring of gliomas and should move this field closer to the goal of improving the management of cancer patients.</p>}},
  author       = {{Indira Chandran, Vineesh and Welinder, Charlotte and Månsson, Ann-Sofie and Offer, Svenja and Freyhult, Eva and Pernemalm, Maria and Lund, Sigrid M and Pedersen, Shona and Lehtiö, Janne and Marko-Varga, Gyorgy and Johansson, Maria C and Englund, Elisabet and Sundgren, Pia C and Belting, Mattias}},
  issn         = {{1078-0432}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{10}},
  pages        = {{3115--3127}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Clinical Cancer Research}},
  title        = {{Ultrasensitive Immunoprofiling of Plasma Extracellular Vesicles Identifies Syndecan-1 as a Potential Tool for Minimally Invasive Diagnosis of Glioma}},
  url          = {{http://dx.doi.org/10.1158/1078-0432.CCR-18-2946}},
  doi          = {{10.1158/1078-0432.CCR-18-2946}},
  volume       = {{25}},
  year         = {{2019}},
}