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

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Abstract
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.
Funding Information
  • ISCIII-FEDER (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • CIBERONC (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • PAIDI-Junta de Andalucia (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • Fundación CRIS contra el cancer (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • Asociación Candela Riera (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • Asociación Pablo Ugarte (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • Juan de la Cierva Incorporación (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • Fundación María García Estrada (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • the University of Seville (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • CIBERONC (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • The European Social Fund (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • Consejeria de Salud (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • the GEIS-Fundación Mari Paz Jiménez Casado (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • the 13ª GEIS-Beca Buesa (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • CRIS (Cancer Research Innovation Spain) (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • Barbara and Wilfried Mohr Foundation (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • the Instituto de Salud Carlos III (ISCIII) (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • Asociación Pablo Ugarte (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)
  • Asociación Candela Riera (PI20/00003, CB16/12/00361, P18-RT-735, IJC-2018-036767-I, CB16/12/00361, Talento Doctores 2020, DOC_01473, PI-0036-2017, PI-0040-2017, PI-0061-2020, PI20CIII/00020, TRPV205/18, TPI-M 1149/13, TVP333-19)

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