Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Molecular Pathology of Sarcomas, 41013 Seville, Spain.
Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41009 Seville, Spain.
Int J Mol Sci. 2022 Aug 4;23(15):8657. doi: 10.3390/ijms23158657.
Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.
内皮糖蛋白（ENG）是间充质干细胞（MSC）的标志物，通常由活跃的内皮细胞表达。这种跨膜糖蛋白被基质金属蛋白酶 14（MMP14）切割。我们之前的工作表明，一类新型的抗 ENG 抗体药物偶联物具有强大的临床前活性，是一种新兴的策略，可以根除尤文肉瘤（ES），这是一种毁灭性的罕见骨/软组织癌症，其起源于 MSC。我们还定义了 ES 中 ENG 和 MMP14 表达之间的相关性。在此，我们表明在一大群 ES 患者中，ENG 表达与预后不良显著相关。此外，ENG/MMP14 在原发性 ES 肿瘤和转移中均频繁表达。为了深入研究它们在 ES 中的功能相关性，我们对体外 ES 模型进行了转录组和蛋白质组分析，揭示了 ENG 和 MMP14 在细胞机械转导中的关键作用。迁移和粘附实验证实，ENG 的缺失会破坏肌动蛋白丝的组装和丝状伪足的形成，同时对细胞铺展产生影响。此外，我们观察到 ENG 通过激活粘着斑信号和蛋白激酶 C 的表达来调节细胞基质相互作用。反过来，MMP14 的缺失通过调节转录细胞外基质动力学，导致 ES 细胞表现出更具黏附性的表型。总之，这些结果表明，ENG 和 MMP14 在调节 ES 细胞的正确铺展机制方面发挥了重要作用，影响了疾病的侵袭性。
