Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell–Matrix Interactions
| Autor: | Pilar Puerto-Camacho, Juan Díaz-Martín, Joaquín Olmedo-Pelayo, Alfonso Bolado-Carrancio, Carmen Salguero-Aranda, Carmen Jordán-Pérez, Marina Esteban-Medina, Inmaculada Álamo-Álvarez, Daniel Delgado-Bellido, Laura Lobo-Selma, Joaquín Dopazo, Ana Sastre, Javier Alonso, Thomas G. P. Grünewald, Carmelo Bernabeu, Adam Byron, Valerie G. Brunton, Ana Teresa Amaral, Enrique De Álava |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | International Journal of Molecular Sciences, Vol 23, Iss 15, p 8657 (2022) |
| Druh dokumentu: | article |
| ISSN: | 1422-0067 1661-6596 |
| DOI: | 10.3390/ijms23158657 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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