Dynamic Landscape of Extracellular Vesicle-Associated Proteins Is Related to Treatment Response of Patients with Metastatic Breast Cancer
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cohort
2.2. Extracellular Vesical Isolation
2.3. Transmission Electron Microscopy
2.4. Nanoparticle Tracking Analysis (NTA)
2.5. Western Blot
2.6. Extracellular Vesicle Protein Digestion and Labelling
2.7. Liquid Chromatography Tandem Mass Spectrometry Analysis
2.8. Data Analysis
3. Results
3.1. Patient and Clinical Characteristics
3.2. Validation of Successful Extracellular Vesicle Isolation
3.3. Quantitative Extracellular Vesical Proteomic Profiling
3.4. Analysis of Extracellular Vesical Associated Proteins of Interest
3.5. Extracellular Vesical Associated Proteins Involved in the Complement Cascade
3.6. Classical, High Abundant Extracellular Vesical Associated Proteins
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Responder | Non-Responder | Mixed-Responder | |
---|---|---|---|
Age | 65 | 68 | 69 |
Sex | Female | Female | Female |
Cancer Staging | IV | IV | IV |
Histopathology | IDC, grade 2 | IDC, grade 3 | IDC, grade 3 |
Receptor status | ER positive PR positive HER2 non-amplified | ER positive PR positive HER2 non-amplified | ER 100% positive PR 10% positive HER2 non-amplified |
Treatment | Endocrine treatment Chemotherapy | Endocrine treatment | Chemotherapy Radiotherapy |
Response | Response at all time points | Progression at all time points | Response then progression |
Increase | Decrease | No Change | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Clinical Response | 1–2 | 1–3 | 2–3 | Overlap ≥ 2 Time Points | 1–2 | 1–3 | 2–3 | Overlap ≥ 2 Time Points | 1–2 | 1–3 | 2–3 | Overlap ≥ 2 Time Points |
Non-Responder | 2 | 55 | 64 | 52 | 12 | 12 | 5 | 8 | 135 | 82 | 80 | 88 |
Responder | 61 | 33 | 34 | 30 | 24 | 14 | 54 | 11 | 64 | 102 | 61 | 59 |
Mixed Responder | 45 | 38 | 15 | 35 | 60 | 53 | 30 | 48 | 44 | 58 | 104 | 61 |
Non-Responder | Responder | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Raw Abundance | Fold Change | Raw Abundance | Fold Change | ||||||||||
Accession | Description | NR1 | NR2 | NR3 | NR1:2 | NR1:3 | NR2:3 | R1 | R2 | R3 | R1:2 | R1:3 | R2:3 |
P04406 | Glyceraldehyde-3-phosphate dehydrogenase | 226.3 | 88.3 | 184.8 | 0.390 | 0.817 | 2.093 | 31.6 | 147.9 | 48.9 | 4.680 | 1.547 | 0.331 |
Q6FI13 | Histone H2A type 2-A | 153.6 | 48.9 | 187 | 0.318 | 1.217 | 3.824 | 30.2 | 140.4 | 83.4 | 4.649 | 2.762 | 0.594 |
Q13201 | Multimerin-1 | 132 | 57.1 | 95.3 | 0.433 | 0.722 | 1.669 | 92 | 38.4 | 215.9 | 0.417 | 2.347 | 5.622 |
P32119 | Peroxiredoxin-2 | 122.4 | 93.9 | 89.9 | 0.767 | 0.734 | 0.957 | 10.4 | 150.5 | 18.6 | 14.471 | 1.788 | 0.124 |
P11277 | Spectrin beta chain | 198.9 | 108.9 | 142.8 | 0.548 | 0.718 | 1.311 | 34.2 | 123.2 | 143.2 | 3.602 | 4.187 | 1.162 |
Non-Responder | Responder | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Raw Abundance | Fold Change | Raw Abundance | Fold Change | ||||||||||
Accession | Description | NR1 | NR2 | NR3 | NR1:2 | NR1:3 | NR2:3 | R1 | R2 | R3 | R1:2 | R1:3 | R2:3 |
Q96H78 | Solute carrier family 25 member 44 | 299.4 | 90.8 | 115 | 0.303 | 0.384 | 1.267 | 82.7 | 44.9 | 78.7 | 0.543 | 0.952 | 1.753 |
P27169 | Paraoxonase/arylesterase 1 | 141.7 | 141.3 | 87 | 0.997 | 0.614 | 0.616 | 95.5 | 58 | 96.1 | 0.607 | 1.006 | 1.657 |
Q96Q89 | Kinesin-like protein KIF20B | 101.5 | 232 | 61.5 | 2.286 | 0.606 | 0.265 | 205 | 65.8 | 155.2 | 0.321 | 0.757 | 2.359 |
P20851 | C4b-binding protein beta chain | 136.3 | 130.5 | 54.2 | 0.957 | 0.398 | 0.415 | 150.7 | 53.4 | 101.5 | 0.354 | 0.674 | 1.901 |
Q8WZ42 | Titin | 151.8 | 66.7 | 94.1 | 0.439 | 0.620 | 1.411 | 54.1 | 113.5 | 141.4 | 2.098 | 2.614 | 1.246 |
P02730 | Band 3 anion transport protein | 175.5 | 90.6 | 76.3 | 0.516 | 0.435 | 0.842 | 59.6 | 88.1 | 109.9 | 1.478 | 1.844 | 1.247 |
P08697 | Alpha-2-antiplasmin | 135.4 | 114.5 | 71.3 | 0.846 | 0.527 | 0.623 | 119.8 | 125.4 | 93.5 | 1.047 | 0.780 | 0.746 |
Non-Responder | Responder | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Raw Abundance | Fold Change | Raw Abundance | Fold Change | ||||||||||
Accession | Description | NR1 | NR2 | NR3 | NR1:2 | NR1:3 | NR2:3 | R1 | R2 | R3 | R1:2 | R1:3 | R2:3 |
O43866 | CD5 antigen-like | 69.1 | 79.9 | 184.8 | 1.156 | 2.674 | 2.313 | 72.5 | 231.2 | 94.6 | 3.189 | 1.305 | 0.409 |
O60814 | Histone H2B type 1-K | 125.8 | 63 | 323.2 | 0.501 | 2.569 | 5.130 | 34.5 | 172.4 | 47.7 | 4.997 | 1.383 | 0.277 |
P02751 | Fibronectin | 64.3 | 80.5 | 126.2 | 1.252 | 1.963 | 1.568 | 60.9 | 139.6 | 78.4 | 2.292 | 1.287 | 0.562 |
P04075 | Fructose-bisphosphate aldolase A | 64.6 | 81.3 | 266.4 | 1.259 | 4.124 | 3.277 | 85.2 | 259.5 | 74.5 | 3.046 | 0.874 | 0.287 |
P06681 | Complement C2 | 95.8 | 78.9 | 189.8 | 0.824 | 1.981 | 2.406 | 88.5 | 200.1 | 64.6 | 2.261 | 0.730 | 0.323 |
P06703 | Protein S100-A6 | 82.8 | 111 | 291.1 | 1.341 | 3.516 | 2.623 | 58.3 | 183.3 | 63.5 | 3.144 | 1.089 | 0.346 |
P07358 | Complement component C8 beta chain | 58.4 | 54.4 | 128.9 | 0.932 | 2.207 | 2.369 | 122.9 | 280.1 | 154.8 | 2.279 | 1.260 | 0.553 |
P12109 | Collagen alpha-1(VI) chain | 64 | 61.1 | 104.5 | 0.955 | 1.633 | 1.710 | 95.6 | 217.3 | 114.1 | 2.273 | 1.194 | 0.525 |
P14618 | Pyruvate kinase PKM | 60.9 | 72.4 | 212.1 | 1.189 | 3.483 | 2.930 | 64.5 | 156.1 | 91 | 2.420 | 1.411 | 0.583 |
P14625 | Endoplasmin | 85.8 | 89.8 | 223.6 | 1.047 | 2.606 | 2.490 | 53.7 | 189.7 | 56.1 | 3.533 | 1.045 | 0.296 |
P55201 | Peregrin | 2.5 | 2.2 | 4.8 | 0.880 | 1.920 | 2.182 | 3.5 | 6.4 | 4.0 | 1.829 | 1.143 | 0.625 |
P62937 | Peptidyl-prolyl cis-trans isomerase A | 81 | 75.5 | 235.3 | 0.932 | 2.905 | 3.117 | 60.3 | 156.9 | 89.9 | 2.602 | 1.491 | 0.573 |
P62979 | Ubiquitin-40S ribosomal protein S27a | 68 | 66.1 | 124.2 | 0.972 | 1.826 | 1.879 | 92.5 | 174.3 | 110.4 | 1.884 | 1.194 | 0.633 |
P68431 | Histone H3.1 | 54.2 | 60.9 | 263.4 | 1.124 | 4.860 | 4.325 | 48.6 | 174.5 | 64.3 | 3.591 | 1.323 | 0.368 |
Q13093 | Platelet-activating factor acetylhydrolase | 97.6 | 89.6 | 189.4 | 0.918 | 1.941 | 2.114 | 89 | 215.2 | 93.1 | 2.418 | 1.046 | 0.433 |
Q8TCU4 | Alstrom syndrome protein 1 | 72.4 | 82.1 | 235.4 | 1.134 | 3.251 | 2.867 | 72.2 | 282.6 | 85.8 | 3.914 | 1.188 | 0.304 |
Q9NZR1 | Tropomodulin-2 | 63.9 | 49.3 | 604.3 | 0.772 | 9.457 | 12.258 | 27.3 | 175.8 | 10.6 | 6.440 | 0.388 | 0.060 |
P08670 | Vimentin | 101.5 | 59.9 | 316.7 | 0.590 | 3.120 | 5.287 | 31.8 | 184.9 | 19.2 | 5.814 | 0.604 | 0.104 |
P23142 | Fibulin-1 | 115.9 | 115.9 | 204.1 | 1.000 | 1.761 | 1.761 | 52.7 | 127.1 | 35.0 | 2.412 | 0.664 | 0.275 |
P23528 | Cofilin-1 | 41.8 | 54 | 229.9 | 1.292 | 5.500 | 4.257 | 71.7 | 101.7 | 81.9 | 1.418 | 1.142 | 0.805 |
P68363 | Tubulin alpha-1B chain | 58.1 | 72.5 | 252.9 | 1.248 | 4.353 | 3.488 | 100.2 | 76.5 | 105.4 | 0.763 | 1.052 | 1.378 |
Q9BWP8 | Collectin-11 | 85.2 | 82.1 | 193.5 | 0.964 | 2.271 | 2.357 | 91 | 132.9 | 97.9 | 1.460 | 1.076 | 0.737 |
Increase | Decrease | No Change | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Clinical Response | 1–2 | 1–3 | 2–3 | Overlap ≥ 2 Time Points | 1–2 | 1–3 | 2–3 | Overlap ≥ 2 Time Points | 1–2 | 1–3 | 2–3 | Overlap ≥ 2 Time Points |
Non-Responder | 11 | 20 | 16 | 0 | 6 | 37 | 35 | 2 | 120 | 80 | 86 | 65 |
Responder | 47 | 30 | 40 | 0 | 32 | 17 | 48 | 0 | 58 | 90 | 49 | 29 |
Mixed-Responder | 33 | 50 | 24 | 2 | 47 | 29 | 7 | 5 | 57 | 58 | 106 | 11 |
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Ruhen, O.; Qu, X.; Jamaluddin, M.F.B.; Salomon, C.; Gandhi, A.; Millward, M.; Nixon, B.; Dun, M.D.; Meehan, K. Dynamic Landscape of Extracellular Vesicle-Associated Proteins Is Related to Treatment Response of Patients with Metastatic Breast Cancer. Membranes 2021, 11, 880. https://doi.org/10.3390/membranes11110880
Ruhen O, Qu X, Jamaluddin MFB, Salomon C, Gandhi A, Millward M, Nixon B, Dun MD, Meehan K. Dynamic Landscape of Extracellular Vesicle-Associated Proteins Is Related to Treatment Response of Patients with Metastatic Breast Cancer. Membranes. 2021; 11(11):880. https://doi.org/10.3390/membranes11110880
Chicago/Turabian StyleRuhen, Olivia, Xinyu Qu, M. Fairuz B. Jamaluddin, Carlos Salomon, Aesha Gandhi, Michael Millward, Brett Nixon, Matthew D. Dun, and Katie Meehan. 2021. "Dynamic Landscape of Extracellular Vesicle-Associated Proteins Is Related to Treatment Response of Patients with Metastatic Breast Cancer" Membranes 11, no. 11: 880. https://doi.org/10.3390/membranes11110880