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Blood plasma derived extracellular vesicles (BEVs): particle purification liquid chromatography (PPLC) and proteomic analysis reveals BEVs as a potential minimally invasive tool for predicting response to breast cancer treatment

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Abstract

Purpose

Circulating blood plasma derived extracellular vesicles (BEVs) containing proteins hold promise for their use as minimally invasive biomarkers for predicting response to cancer therapy. The main goal of this study was to establish the efficiency and utility of the particle purification liquid chromatography (PPLC) BEV isolation method and evaluate the role of BEVs in predicting breast cancer (BC) patient response to neoadjuvant chemotherapy (NAC).

Methods

PPLC isolation was used to separate BEVs from non-EV contaminants and characterize BEVs from 17 BC patients scheduled to receive NAC. Using LC–MS/MS, we compared the proteome of PPLC-isolated BEVs from patients (n = 7) that achieved a pathological complete response (pCR) after NAC (responders [R]) to patients (n = 10) who did not achieve pCR (non-responders [NR]). Luminal MCF7 and basaloid MDA-MB-231 BC cells were treated with isolated BEVs and evaluated for metabolic activity by MTT assay.

Results

NR had elevated BEV concentrations and negative zeta potential (ζ-potential) prior to receipt of NAC. Eight proteins were enriched in BEVs of NR. GP1BA (CD42b), PECAM-1 (CD31), CAPN1, HSPB1 (HSP27), and ANXA5 were validated using western blot. MTT assay revealed BEVs from R and NR patients increased metabolic activity of MCF7 and MDA-MB-231 BC cells and the magnitude was highest in MCF7s treated with NR BEVs.

Conclusion

PPLC-based EV isolation provides a preanalytical separation process for BEVs devoid of most contaminants. Our findings suggest that PPLC-isolated BEVs and the five associated proteins may be established as predictors of chemoresistance, and thus serve to identify NR to spare them the toxic effects of NAC.

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Data availability

Spectral counts and precursor abundances dataset with peptide spectrum match annotations are attached to this manuscript as additional files.

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Acknowledgements

This work was supported by the National Institute on Drug Abuse (NIDA), grants DA042348, DA050169, and DA053643 to CMO. This work was partially supported by the Scholars in Biomedical Sciences T32GM127253 award to FAA. This work was supported, in part, by the Stony Brook University Advanced Energy Research and Technology Center and Proteomics Core, and Iowa Hybridoma Bank. We thank the patients for donating blood. We particularly thank Dr. John Haley, the director of the Stony Brook University Proteomics Core.

Funding

This work received support from National Institute on Drug Abuse (NIDA) to Chioma M Okeoma (Grants, DA042348, DA050169, and DA053643). This work was also supported by a Stony Brook University start-up fund granted to Chioma M Okeoma. 

Author information

Author notes

  1. Hussein Kaddour

    Present address: Regeneron Pharmaceuticals, Inc, Tarrytown, NY, 10591, USA

  2. Yuan Lyu

    Present address: Medical Research Center, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

  3. Christina Preece & Patricia Thompson

    Present address: Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA

  4. Chioma M. Okeoma

    Present address: Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY, 10595-1524, USA

Authors and Affiliations

  1. Department of Pharmacology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, 11794-8651, USA

    Folnetti A. Alvarez, Hussein Kaddour, Yuan Lyu & Chioma M. Okeoma

  2. Department of Pathology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, 11794-8651, USA

    Christina Preece & Patricia Thompson

  3. Department of Medicine, Division of Hematology and Medical Oncology, Stony Brook University, Stony Brook, NY, 11794-8651, USA

    Jules Cohen, Lea Baer & Alison T. Stopeck

  4. Stony Brook University Cancer Center, Stony Brook, NY, 11794-8651, USA

    Jules Cohen, Lea Baer, Alison T. Stopeck & Patricia Thompson

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  1. Folnetti A. Alvarez
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Contributions

CMO, PT, FAA: Conceptualization; CMO, PT, FAA, HK, YL, CP: Methodology; FAA, HK: Validation; CMO, PT, FAA, HK, YL, CP: Formal Analysis; CMO, PT, FAA, HK, YL, CP: Investigation; CMO, PT: Resources; JC, LB, ATS: Recruitment; FAA, HK, YL, CP: Data Curation; CMO, PT, FAA, HK, JC, LB, ATS, YL CP: Writing—Original Draft Preparation; FAA, CMO, PT, HK: Writing—Review & Editing; CMO,PT: Supervision; CMO: Project Administration; CMO, PT: Funding Acquisition. All authors participated in manuscript preparation and approved the final version of the manuscript.

Corresponding author

Correspondence to Chioma M. Okeoma.

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This study was conducted according to university regulations approved by Stony Brook University Institutional Review Boards (IRB # 860033).

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Individuals who met the inclusion and exhibit none of the exclusion criteria and who gave written informed consent were included in the study.

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Alvarez, F.A., Kaddour, H., Lyu, Y. et al. Blood plasma derived extracellular vesicles (BEVs): particle purification liquid chromatography (PPLC) and proteomic analysis reveals BEVs as a potential minimally invasive tool for predicting response to breast cancer treatment. Breast Cancer Res Treat 196, 423–437 (2022). https://doi.org/10.1007/s10549-022-06733-x

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