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Anal Chem. 2018 Nov 20;90(22):13178-13182. doi: 10.1021/acs.analchem.8b03756. Epub 2018 Nov 1.

MALDI-MS Protein Profiling of Chemoresistance in Extracellular Vesicles of Cancer Cells.

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Department of Biomedical Imaging and Image-guided Therapy , Medical University of Vienna , Währinger Gürtel 18-20 , 1090 Vienna , Austria.
Comprehensive Cancer Center of the Medical University of Vienna , Spitalgasse 23 , 1090 Vienna , Austria.
Shimadzu/Kratos Analytical , Trafford Wharf Road , M17 1GP Manchester , United Kingdom.
Clover Bioanalytical Software SL , Avda De La Innovacion 1 , 18016 Granada , Spain.
Department of Paediatrics, Molecular Neuro-Oncology Research Unit , Medical University of Vienna , Währinger Gürtel 18-20 , 1090 Vienna , Austria.
Department of Medicine I, Clinical Division of Oncology , Medical University of Vienna , Währinger Gürtel 18-20 , 1090 Vienna , Austria.


Cancer cells communicate with the whole organism via extracellular vesicles (EVs), which propagate molecular information in support of the malignant phenotype. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was employed for protein profiling of EVs derived from CCL-228 as the primary colon tumor, the lymph node metastasis CCL-227, and subclones resistant to 5, 25, and 125 μM 5-fluorouracil (FU). EVs were harvested from cell culture supernatant by ultracentrifugation to serve as a model for circulating cancer cell-derived biomarker carriers from body fluids (i.e., liquid biopsy). Protein mass spectra were recorded using standard MALDI matrixes (e.g., CHCA, sinapinic acid) in the range m/ z 2000-20000 on different MALDI-TOF-MS systems and subjected to multivariate data analysis . By using hierarchical clustering, PCA and PLS-DA, discriminatory protein patterns of the EVs from the different cell populations were obtained. Peaks in the range  m/ z 2000-6500 and m/ z 5500-15500 were found to be unique to EVs and the cells, respectively. This clearly demonstrates the differential expression of proteins in EVs as the result of an increasing chemoresistance of their parent cells. The sensitivity of the MALDI-MS based assay was in the low μg/mL (≈1.2-5 × 1010 particles/mL) range. Consequently, our MALDI-MS protein profiling approach shows the potential to serve as novel tool for minimally invasive cancer diagnostics and chemotherapy monitoring in the future, e.g., for early detection of therapy resistance without biopsy.

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