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Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions.

Pilar Puerto-Camacho1, Juan Díaz-Martín1,2, Joaquín Olmedo-Pelayo1,2

  • 1Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Molecular Pathology of Sarcomas, 41013 Seville, Spain.

International Journal of Molecular Sciences
|August 12, 2022
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Summary

Endoglin (ENG) and matrix metalloproteinase 14 (MMP14) are linked to poor prognosis in Ewing sarcoma (ES). Targeting these proteins may impact ES cell spreading and disease aggressiveness.

Keywords:
Ewing sarcomaendoglinextracellular matrixmechano-transduction

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Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Endoglin (ENG) is a mesenchymal stem cell (MSC) marker expressed by active endothelium and shed by matrix metalloproteinase 14 (MMP14).
  • Previous research showed anti-ENG antibody-drug conjugates have preclinical activity against Ewing sarcoma (ES), a rare bone/soft tissue cancer with a putative MSC origin.
  • A correlation between ENG and MMP14 expression in ES was previously established.

Purpose of the Study:

  • To investigate the prognostic significance of ENG expression in ES patients.
  • To explore the functional roles of ENG and MMP14 in ES cell biology, particularly in cell mechano-transduction, migration, and adhesion.
  • To understand the impact of ENG and MMP14 on ES aggressiveness.

Main Methods:

  • Analysis of ENG expression in a large cohort of ES patients to correlate with prognosis.
  • Transcriptomic and proteomic profiling of in vitro ES models.
  • Migration, adhesion, and cell spreading assays.
  • Assessment of focal adhesion signaling and protein kinase C expression.

Main Results:

  • ENG expression is significantly associated with a dismal prognosis in ES patients.
  • Both ENG and MMP14 are frequently expressed in primary ES tumors and metastases.
  • ENG and MMP14 play a key role in cell mechano-transduction, affecting actin filament assembly, filopodia formation, and cell spreading.
  • ENG regulates cell-matrix interaction via focal adhesion signaling and protein kinase C.
  • MMP14 modulates extracellular matrix dynamics, contributing to a more adhesive ES cell phenotype.

Conclusions:

  • ENG and MMP14 are critical for proper cell spreading machinery in ES cells.
  • These proteins significantly impact the aggressiveness of Ewing sarcoma.
  • Targeting ENG and MMP14 represents a potential therapeutic strategy for ES.