Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions.
Pilar Puerto-CamachoJuan Díaz MartínJoaquín Olmedo-PelayoAlfonso Bolado-CarrancioCarmen Salguero-ArandaCarmen Jordán-PérezMarina Esteban-MedinaInmaculada Álamo-ÁlvarezDaniel Delgado-BellidoLaura Lobo-SelmaJoaquín DopazoAna SastreJavier AlonsoThomas G P GrünewaldCarmelo BernabéuAdam ByronValerie G BruntonAna Teresa AmaralEnrique de ÁlavaPublished in: International journal of molecular sciences (2022)
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.
Keyphrases
- single cell
- cell migration
- cell therapy
- poor prognosis
- extracellular matrix
- induced apoptosis
- soft tissue
- end stage renal disease
- chronic kidney disease
- rna seq
- squamous cell carcinoma
- protein kinase
- cell cycle arrest
- stem cells
- signaling pathway
- ejection fraction
- bone mineral density
- long non coding rna
- escherichia coli
- patient reported outcomes
- postmenopausal women
- endoplasmic reticulum stress
- pseudomonas aeruginosa
- single molecule
- living cells
- pi k akt
- fluorescent probe
- prognostic factors