Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 15, Pages -Publisher
MDPI
DOI: 10.3390/ijms23158657
Keywords
Ewing sarcoma; endoglin; mechano-transduction; extracellular matrix
Funding
- ISCIII-FEDER [PI20/00003]
- CIBERONC [CB16/12/00361]
- PAIDI-Junta de Andalucia [P18-RT-735]
- Fundacion CRIS Contra el Cancer
- Asociacion Candela Riera
- Juan de la Cierva Incorporacion fellowship [IJC-2018036767-I]
- Fundacion Maria Garcia Estrada
- University of Seville
- European Social Fund
- Junta de Andalucia [DOC_01473]
- Consejeria de Salud (Junta de Andalucia) [PI-0036-2017, PI-0040-2017, PI-0061-2020]
- Asociacion Pablo Ugarte
- GEIS-Fundacion Mari Paz Jimenez Casado (IV beca trienal)
- 13a GEIS-Beca Buesa
- CRIS (Cancer Research Innovation Spain)
- Barbara and Wilfried Mohr Foundation
- Instituto de Salud Carlos III (ISCIII) [PI20CIII/00020]
- Asociacion Pablo Ugarte [TRPV205/18, TPI-M 1149/13]
- Asociacion Todos Somos Ivan
- Fundacion Sonrisa de Alex [TVP333-19]
Ask authors/readers for more resources
This study found that the expression of endoglin (ENG) and matrix metalloproteinase 14 (MMP14) is significantly associated with poor prognosis in Ewing sarcoma (ES) patients. Further experiments demonstrated the key role of ENG and MMP14 in cell mechanotransduction and their impact on migration and adhesion in ES cells.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available