Proteomic profiles of peritoneal fluid-derived small extracellular vesicles correlate with patient outcome in ovarian cancer
Miguel Quiralte, Arantzazu Barquín, Mónica Yagüe-Fernández, Paloma Navarro, Tatiana P. Grazioso, Elena Sevillano-Fernández, Juan F. Rodriguez-Moreno, Alejandra Balarezo-Saldivar, Héctor Peinado, Elena Izquierdo, Carlos Millán, Irene López-Carrasco, Mario Prieto, Rodrigo Madurga, Ismael Fernández-Miranda, Sergio Ruiz-Llorente, Jesús García-Donas
Miguel Quiralte, Arantzazu Barquín, Mónica Yagüe-Fernández, Paloma Navarro, Tatiana P. Grazioso, Elena Sevillano-Fernández, Juan F. Rodriguez-Moreno, Alejandra Balarezo-Saldivar, Héctor Peinado, Elena Izquierdo, Carlos Millán, Irene López-Carrasco, Mario Prieto, Rodrigo Madurga, Ismael Fernández-Miranda, Sergio Ruiz-Llorente, Jesús García-Donas
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Research Article Oncology

Proteomic profiles of peritoneal fluid-derived small extracellular vesicles correlate with patient outcome in ovarian cancer

Abstract

Cancer-derived small extracellular vesicles (sEVs) are capable of modifying the tumor microenvironment and promoting tumor progression. Ovarian cancer (OvCa) is a lethal malignancy that preferentially spreads through the abdominal cavity. Thus, the secretion of such vesicles into the peritoneal fluid could be a determinant factor in the dissemination and behavior of this disease. We designed a prospective observational study to assess the impact of peritoneal fluid–derived sEVs (PFD-sEVs) in OvCa clinical outcome. For this purpose, 2 patient cohorts were enrolled: patients with OvCa who underwent a diagnostic or cytoreductive surgery and nononcological patients, who underwent abdominal surgery for benign gynecological conditions and acted as the control group. Systematic extraction of PFD-sEVs from surgical samples enabled us to observe significant quantitative and qualitative differences associated with cancer diagnosis, disease stage, and platinum chemosensitivity. Proteomic profiling of PFD-sEVs led to the identification of molecular pathways and proteins of interest and to the biological validation of S100A4 and STX5. In addition, unsupervised analysis of PFD-sEV proteomic profiles in high-grade serous ovarian carcinomas (HGSOCs) revealed 2 clusters with different outcomes in terms of overall survival. In conclusion, comprehensive characterization of PFD-sEV content provided a prognostic value with potential implications in HGSOC clinical management.

Authors

Miguel Quiralte, Arantzazu Barquín, Mónica Yagüe-Fernández, Paloma Navarro, Tatiana P. Grazioso, Elena Sevillano-Fernández, Juan F. Rodriguez-Moreno, Alejandra Balarezo-Saldivar, Héctor Peinado, Elena Izquierdo, Carlos Millán, Irene López-Carrasco, Mario Prieto, Rodrigo Madurga, Ismael Fernández-Miranda, Sergio Ruiz-Llorente, Jesús García-Donas

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Figure 4

Correlation clustering map depicting the unsupervised analysis for the PFD-EV proteins profiled by mass spectrometry.

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Correlation clustering map depicting the unsupervised analysis for the P...
(A) Unsupervised analysis for all cases and controls. At right, the main clusters (1, 2, and 3) and subclusters (2A–C and 3A–B) and the key clinical characteristics of the samples being compared are highlighted (controls [SC, serous ovarian cystadenoma; MC, mucinous ovarian cystadenoma; UM, uterine myoma; EH, endometrial hyperplasia] vs. OvCa tumoral sample; HGSOC vs. non-HGSOC [E, endometrioid; LGS, low-grade serous; M, mucinous; CC, clear cell]). Correlation clusters with highest ratios are labeled in light or dark green boxes. (B) Unsupervised analysis for HGSOC cases and controls. At right, the main carcinoma clusters (S-1, n = 10; and S-2, n = 13) and the key clinical characteristics of the samples being compared are highlighted (controls [SC, MC, UM, and EH] vs. HGSOC; surgical procedures: primary, interval, or recurrence surgeries; HRD status: BRCA1/2 pathogenic variants, alterations in HRD-related genes, HR proficient, or not applicable [NA]; platinum sensitivity: platinum-sensitive, platinum-resistant, or NA; surgical outcome: R0, R1, or NA). Main correlation subclusters for both S-1 and S-2 are depicted in dark green boxes, which are mainly constituted by 55% relapses (subc. S-1, 5/9) or 80% diagnostic/primary specimens (subc. S-2, 8/10). Light green boxes include the highest correlated samples and are associated exclusively with relapses (average correlation, 0.76) or diagnostic samples (average correlation, 0.82). The color bar on the left indicates the degree of correlation between 2 samples under study, with a value of 1 (dark red) indicating an identical sample in terms of protein cargo and –1 (dark blue) indicating potential samples with completely opposite profiles. Asterisks denote serial samples (C516 and C618) from one HGSOC case.