Project description:Endoglin (ENG) is a mesenchymal stem cell (MSC) marker highly expressed mainly in active endothelium and certain cancer types. This transmembrane protein is shed to the extracellular compartment by the matrix metalloproteinase 14 (MMP14). Previously, ENG was identified in patient samples from Ewing sarcoma (ES), a bone/soft tissue neoplasia with a putative MSC origin. ES is a predominant paediatric malignancy with high incidence of metastasis at diagnosis, around 30% patients, associated with poor prognosis. This scenario is worsened by the fact that current chemotherapeutic treatments fail to achieve a significant impact on advanced disease. On-target therapies emerge strongly appealing in the clinical setting of ES. Given that a high percentage of patients presented ENG expression at the cell surface, antibody-drug conjugates (ADCs) against ENG were studied. ,. Anti-ENG ADCs exerted an ENG-dependent and dose-dependent anti-proliferative effect in , both in vivo and in vitro ES models. These results suggest that the use of ENG-ADC might have potential benefits in in ES . As the expression of ENG and MMP14 was variable amongst ES patients, a survival study was assessed in a cohort of 82 patients categorised according to their clinical stage (primary, post chemotherapy primary, metastasis and relapse). Both ENG and MMP14 were associated with worse prognosis. Functional assays revealed that ENG regulates migration, probably through the correct assembly of actin in stress fibres and filopodia, with a concomitant effect on the adhesive capacity of the cell. Furthermore, ENG was confirmed to be important in the activation of focal adhesion signalling, by favouring focal adhesion kinase phosphorylation and protein kinase C expression. verall, these results suggest that ENG exerts a main role as an adaptor protein in the correct migration machinery of ES cells.
Project description:Endoglin (ENG) is a mesenchymal stem cell (MSC) marker highly expressed mainly in active endothelium and certain cancer types. This transmembrane protein is shed to the extracellular compartment by the matrix metalloproteinase 14 (MMP14). Previously, ENG was identified in patient samples from Ewing sarcoma (ES), a bone/soft tissue neoplasia with a putative MSC origin. ES is a predominant paediatric malignancy with high incidence of metastasis at diagnosis, around 30% patients, associated with poor prognosis. This scenario is worsened by the fact that current chemotherapeutic treatments fail to achieve a significant impact on advanced disease. On-target therapies emerge strongly appealing in the clinical setting of ES. Given that a high percentage of patients presented ENG expression at the cell surface, antibody-drug conjugates (ADCs) against ENG were studied. ,. Anti-ENG ADCs exerted an ENG-dependent and dose-dependent anti-proliferative effect in , both in vivo and in vitro ES models. These results suggest that the use of ENG-ADC might have potential benefits in in ES . As the expression of ENG and MMP14 was variable amongst ES patients, a survival study was assessed in a cohort of 82 patients categorised according to their clinical stage (primary, post chemotherapy primary, metastasis and relapse). Both ENG and MMP14 were associated with worse prognosis. Functional assays revealed that ENG regulates migration, probably through the correct assembly of actin in stress fibres and filopodia, with a concomitant effect on the adhesive capacity of the cell. Furthermore, ENG was confirmed to be important in the activation of focal adhesion signalling, by favouring focal adhesion kinase phosphorylation and protein kinase C expression. verall, these results suggest that ENG exerts a main role as an adaptor protein in the correct migration machinery of ES cells.
Project description:Endoglin (ENG) is a mesenchymal stem cell (MSC) marker highly expressed mainly in active endothelium and certain cancer types. This transmembrane protein is shed to the extracellular compartment by the matrix metalloproteinase 14 (MMP14). Previously, ENG was identified in patient samples from Ewing sarcoma (ES), a bone/soft tissue neoplasia with a putative MSC origin. ES is a predominant paediatric malignancy with high incidence of metastasis at diagnosis, around 30% patients, associated with poor prognosis. This scenario is worsened by the fact that current chemotherapeutic treatments fail to achieve a significant impact on advanced disease. On-target therapies emerge strongly appealing in the clinical setting of ES. Given that a high percentage of patients presented ENG expression at the cell surface, antibody-drug conjugates (ADCs) against ENG were studied. ,. Anti-ENG ADCs exerted an ENG-dependent and dose-dependent anti-proliferative effect in , both in vivo and in vitro ES models. These results suggest that the use of ENG-ADC might have potential benefits in in ES . As the expression of ENG and MMP14 was variable amongst ES patients, a survival study was assessed in a cohort of 82 patients categorised according to their clinical stage (primary, post chemotherapy primary, metastasis and relapse). Both ENG and MMP14 were associated with worse prognosis. Functional assays revealed that ENG regulates migration, probably through the correct assembly of actin in stress fibres and filopodia, with a concomitant effect on the adhesive capacity of the cell. Furthermore, ENG was confirmed to be important in the activation of focal adhesion signalling, by favouring focal adhesion kinase phosphorylation and protein kinase C expression. verall, these results suggest that ENG exerts a main role as an adaptor protein in the correct migration machinery of ES cells.
Project description:Endoglin (ENG) is a mesenchymal stem cell (MSC) marker highly expressed mainly in active endothelium and certain cancer types. This transmembrane protein is shed to the extracellular compartment by the matrix metalloproteinase 14 (MMP14). Previously, ENG was identified in patient samples from Ewing sarcoma (ES), a bone/soft tissue neoplasia with a putative MSC origin. ES is a predominant paediatric malignancy with high incidence of metastasis at diagnosis, around 30% patients, associated with poor prognosis. This scenario is worsened by the fact that current chemotherapeutic treatments fail to achieve a significant impact on advanced disease. On-target therapies emerge strongly appealing in the clinical setting of ES. Given that a high percentage of patients presented ENG expression at the cell surface, antibody-drug conjugates (ADCs) against ENG were studied. ,. Anti-ENG ADCs exerted an ENG-dependent and dose-dependent anti-proliferative effect in , both in vivo and in vitro ES models. These results suggest that the use of ENG-ADC might have potential benefits in in ES . As the expression of ENG and MMP14 was variable amongst ES patients, a survival study was assessed in a cohort of 82 patients categorised according to their clinical stage (primary, post chemotherapy primary, metastasis and relapse). Both ENG and MMP14 were associated with worse prognosis. Functional assays revealed that ENG regulates migration, probably through the correct assembly of actin in stress fibres and filopodia, with a concomitant effect on the adhesive capacity of the cell. Furthermore, ENG was confirmed to be important in the activation of focal adhesion signalling, by favouring focal adhesion kinase phosphorylation and protein kinase C expression. verall, these results suggest that ENG exerts a main role as an adaptor protein in the correct migration machinery of ES cells.
Project description:Endoglin (ENG) is a mesenchymal stem cell (MSC) marker highly expressed mainly in active endothelium and certain cancer types. This transmembrane protein is shed to the extracellular compartment by the matrix metalloproteinase 14 (MMP14). Previously, ENG was identified in patient samples from Ewing sarcoma (ES), a bone/soft tissue neoplasia with a putative MSC origin. ES is a predominant paediatric malignancy with high incidence of metastasis at diagnosis, around 30% patients, associated with poor prognosis. This scenario is worsened by the fact that current chemotherapeutic treatments fail to achieve a significant impact on advanced disease. On-target therapies emerge strongly appealing in the clinical setting of ES. Given that a high percentage of patients presented ENG expression at the cell surface, antibody-drug conjugates (ADCs) against ENG were studied. ,. Anti-ENG ADCs exerted an ENG-dependent and dose-dependent anti-proliferative effect in , both in vivo and in vitro ES models. These results suggest that the use of ENG-ADC might have potential benefits in in ES . As the expression of ENG and MMP14 was variable amongst ES patients, a survival study was assessed in a cohort of 82 patients categorised according to their clinical stage (primary, post chemotherapy primary, metastasis and relapse). Both ENG and MMP14 were associated with worse prognosis. Functional assays revealed that ENG regulates migration, probably through the correct assembly of actin in stress fibres and filopodia, with a concomitant effect on the adhesive capacity of the cell. Furthermore, ENG was confirmed to be important in the activation of focal adhesion signalling, by favouring focal adhesion kinase phosphorylation and protein kinase C expression. verall, these results suggest that ENG exerts a main role as an adaptor protein in the correct migration machinery of ES cells.
Project description:We identify and validate an Ewing sarcoma-specific CRC, which is under control of EWS-FLI1. Formed by KLF15, TCF4 and NKX2-2, this CRC apparatus coordinates the gene expression programs in Ewing sarcoma cells. These data advance the understanding of the mechanistic basis of transactional dysregulation in Ewing sarcoma, and provide potential novel therapeutic strategies against this malignancy.
Project description:This SuperSeries is composed of the following subset Series: GSE36857: Goldengate Methylation analysis: Ewing Sarcoma GSE36858: 5- AZA treatment of EWS cell lines Refer to individual Series
Project description:Ewing sarcoma is an aggressive pediatric small round cell tumor that predominantly occurs in bone. Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS/FLI interacts with numerous lineage-essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS/FLI binds the osteogenic transcription factor RUNX2 and prevents osteoblast differentiation. In this study, we investigated the role of another Runt-domain protein, RUNX3, in Ewing sarcoma. RUNX3 participates in mesenchymal-derived bone formation and is a context dependent tumor suppressor and oncogene. RUNX3 was detected in all Ewing sarcoma cells examined, whereas RUNX2 was detected in only 73% of specimens. Like RUNX2, RUNX3 binds to EWS/FLI via its Runt domain. EWS/FLI prevented RUNX3 from activating the transcription of a RUNX-responsive reporter, p6OSE2. Stable suppression of RUNX3 expression in the Ewing sarcoma cell line A673 delayed colony growth in anchorage independent soft agar assays and reversed expression of EWS/FLI-responsive genes. These results demonstrate an important role for RUNX3 in Ewing sarcoma. RNA-seq to compare transcriptiome of control A673 ewing sarcoma cells stably expression a non-target or RUNX3 shRNA