Irmer Barnabas, Angenendt Allegra, Camoin Luc, Audebert Stéphane, Geyer Christiane, Gerwing Mirjam, Spiessbach Hanna, Hebel Mira, Baudelet Émilie, Wlochowitz Darius, Hansen Uwe, Bleckmann Annalen, Zimmermann Pascale, Menck Kerstin
Department of Medicine A, Hematology, Oncology, and Pneumology, University of Muenster, Muenster, Germany.
West German Cancer Center, University Hospital Muenster, Muenster, Germany.
J Extracell Vesicles. 2025 Aug;14(8):e70133. doi: 10.1002/jev2.70133.
Despite extensive proof for the tumour-supporting function of cancer-derived small extracellular vesicles (sEVs), attributions of pathological effects to specific sEV subpopulations are poorly described. In this study, we aimed to characterise a distinct sEV species under the control of Syntenin, a key regulator of endosomal sEV biogenesis, regarding its proteomic cargo and pro-tumourigenic functions. Using mass spectrometry (MS), we detected 178 down- and 236 up-regulated proteins on sEVs from breast cancer cells upon Syntenin knockout (KO). Pathway enrichment analysis suggested that Syntenin depletion was particularly associated with adhesion-related processes. Accordingly, sEVs from Syntenin-deficient 4T1 and MCF-7 breast cancer cells showed a reduced expression of several focal adhesion and cell-cell junction proteins. Syntenin silencing reduced the Fibronectin-binding capacity of sEVs from both cell lines, which was mediated by sEV-associated Integrin alpha-V/beta-3 (αβ). Compared to sEVs from wildtype cells, Syntenin KO sEVs showed decreased tropism towards the Fibronectin-rich liver microenvironment in vivo, provided less adhesive support for 4T1 cells and thereby failed to induce cancer cell migration, which appeared to be independent of EV uptake. In summary, this study revealed that Syntenin has a large-scale effect on the proteomic cargo of sEVs and regulates their adhesive, organotropic and pro-migratory properties in breast cancer.
尽管有大量证据表明癌症衍生的小细胞外囊泡（sEVs）具有肿瘤支持功能，但对特定sEV亚群的病理效应归因却鲜有描述。在本研究中，我们旨在表征一种在内体sEV生物发生的关键调节因子Syntenin控制下的独特sEV种类，研究其蛋白质组学成分和促肿瘤功能。通过质谱（MS）分析，我们在Syntenin基因敲除（KO）的乳腺癌细胞的sEVs上检测到178种下调蛋白和236种上调蛋白。通路富集分析表明，Syntenin缺失尤其与黏附相关过程有关。因此，来自Syntenin缺陷的4T1和MCF-7乳腺癌细胞的sEVs显示出几种粘着斑和细胞间连接蛋白的表达降低。Syntenin沉默降低了两种细胞系sEVs的纤连蛋白结合能力，这是由sEV相关的整合素α-V/β-3（αβ）介导的。与野生型细胞的sEVs相比，Syntenin KO sEVs在体内对富含纤连蛋白的肝脏微环境的趋向性降低，为4T1细胞提供的黏附支持减少，从而无法诱导癌细胞迁移，这似乎与EV摄取无关。总之，本研究表明Syntenin对sEVs的蛋白质组学成分有大规模影响，并调节其在乳腺癌中的黏附、器官趋向性和促迁移特性。
