Identity of ovarian cancers shaped through transfer of exosome-derived microRNAs

Ovarian cancer represents a highly lethal disease that poses a substantial burden for females, with four main molecular subtypes carrying distinct clinical outcomes. Here, Sichuan University researchers demonstrated that plasma cells, a subset of antibody-producing B cells, were enriched in the mesenchymal subtype of high-grade serous ovarian cancers (HGSCs). Plasma cell abundance correlated with the density of mesenchymal cells in clinical specimens of HGSCs. Coculture of nonmesenchymal ovarian cancer cells and plasma cells induced a mesenchymal phenotype of tumor cells in vitro and in vivo. Phenotypic switch was mediated by the transfer of plasma cell–derived exosomes containing miR-330-3p into nonmesenchymal ovarian cancer cells. Exosome-derived miR-330-3p increased expression of junctional adhesion molecule B in a noncanonical fashion. Depletion of plasma cells by bortezomib reversed the mesenchymal characteristics of ovarian cancer and inhibited in vivo tumor growth. Collectively, this work suggests targeting plasma cells may be a novel approach for ovarian cancer therapy.

Plasma cell exosomal miR-330-3p could be transferred to ovarian cancer

(A) Schematic diagram of plasma cells and ovarian cancer cells cocultured in six-well plates. (B) Ovarian cancer cells were cocultured in the absence or presence of primary PKH67-labeled plasma cells (green). Nuclei were stained with DAPI (blue) (n = 3 for each group). Scale bar, 20 μm. (C) Western blot analysis for CD63, CD81, and β-actin in plasma cell exosomes (n = 3 for each group). (D) Electron micrograph of plasma cell exosomes shows the morphological size (50 to 200 nm). Scale bar, 100 nm. (E) Size distribution of exosomes was measured using NanoSight analysis. (F and G) Immunofluorescent images of PKH67 abrogation in ovarian cancer cells with respective treatment. Scale bar, 20 μm. Statistical chart was plotted (n = 3 for each group). (H) Scheme chart for small RNA sequencing in plasma cell exosomes in patients with ovarian cancer. tRNA, transfer RNA; rRNA, ribosomal RNA; snRNA, small nuclear RNA; snoRNA, small nucleolar RNA; piRNA, Piwi-interacting RNA.(I) Venn diagram for overlapped miRNAs identified in ovarian cancer plasma cell exosomes. (J) Heatmap for unsupervised hierarchical clustering of GSE73582 dataset using plasma cell exosome–specific miRNA panel as classifiers. (K) Cellular programs enriched by GSEA for plasma cell exosome–specific miRNAs represented using Enrichment Map. (L) The univariate regression analyses of the identified top miRNAs associated with patient survival, OC179 (GSE73581), n = 179. CI, confidence interval. (M and N) Fluorescence diagram shows subcellular localization of miR-330-3p (yellow arrowheads) (n = 3 to 4 for each group). Scale bar, 20 μm. In (G), data are shown as mean ± SEM. All statistical significance was determined by a two-tailed, unpaired Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.

Yang Z, Wang W, Zhao L, Wang X, Gimple RC, Xu L, Wang Y, Rich JN, Zhou S. (2021) Plasma cells shape the mesenchymal identity of ovarian cancers through transfer of exosome-derived microRNAs. Sci Adv 7(9):eabb0737. [article]

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