The endochondral bone protein CHM1 sustains an undifferentiated, invasive phenotype, promoting lung metastasis in Ewing sarcoma
Ewing sarcomas (ES) are highly malignant, osteolytic bone or soft tissue tumors, which are characterized by EWS–ETS translocations and early metastasis to lung and bone. In this study, we investigated the role of the BRICHOS chaperone domain‐containing endochondral bone protein chondromodulin I (CHM...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2017-09-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12057 |
| _version_ | 1811206876966158336 |
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| author | Kristina vonHeyking Julia Calzada‐Wack Stefanie Göllner Frauke Neff Oxana Schmidt Tim Hensel David Schirmer Annette Fasan Irene Esposito Carsten Müller‐Tidow Poul H. Sorensen Stefan Burdach Günther H. S. Richter |
| author_facet | Kristina vonHeyking Julia Calzada‐Wack Stefanie Göllner Frauke Neff Oxana Schmidt Tim Hensel David Schirmer Annette Fasan Irene Esposito Carsten Müller‐Tidow Poul H. Sorensen Stefan Burdach Günther H. S. Richter |
| author_sort | Kristina vonHeyking |
| collection | DOAJ |
| description | Ewing sarcomas (ES) are highly malignant, osteolytic bone or soft tissue tumors, which are characterized by EWS–ETS translocations and early metastasis to lung and bone. In this study, we investigated the role of the BRICHOS chaperone domain‐containing endochondral bone protein chondromodulin I (CHM1) in ES pathogenesis. CHM1 is significantly overexpressed in ES, and chromosome immunoprecipitation (ChIP) data demonstrate CHM1 to be directly bound by an EWS–ETS translocation, EWS‐FLI1. Using RNA interference, we observed that CHM1 promoted chondrogenic differentiation capacity of ES cells but decreased the expression of osteolytic genes such as HIF1A, IL6, JAG1, and VEGF. This was in line with the induction of the number of tartrate‐resistant acid phosphatase (TRAP+)‐stained osteoclasts in an orthotopic model of local tumor growth after CHM1 knockdown, indicating that CHM1‐mediated inhibition of osteomimicry might play a role in homing, colonization, and invasion into bone tissues. We further demonstrate that CHM1 enhanced the invasive potential of ES cells in vitro. This invasiveness was in part mediated via CHM1‐regulated matrix metallopeptidase 9 expression and correlated with the observation that, in an xenograft mouse model, CHM1 was essential for the establishment of lung metastases. This finding is in line with the observed increase in CHM1 expression in patient specimens with ES lung metastases. Our results suggest that CHM1 seems to have pleiotropic functions in ES, which need to be further investigated, but appears to be essential for the invasive and metastatic capacities of ES. |
| first_indexed | 2024-04-12T03:55:17Z |
| format | Article |
| id | doaj.art-a89b68b466eb4b23a7712fee193d0f90 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-12T03:55:17Z |
| publishDate | 2017-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-a89b68b466eb4b23a7712fee193d0f902022-12-22T03:48:52ZengWileyMolecular Oncology1574-78911878-02612017-09-011191288130110.1002/1878-0261.12057The endochondral bone protein CHM1 sustains an undifferentiated, invasive phenotype, promoting lung metastasis in Ewing sarcomaKristina vonHeyking0Julia Calzada‐Wack1Stefanie Göllner2Frauke Neff3Oxana Schmidt4Tim Hensel5David Schirmer6Annette Fasan7Irene Esposito8Carsten Müller‐Tidow9Poul H. Sorensen10Stefan Burdach11Günther H. S. Richter12Laboratory for Functional Genomics and Transplantation BiologyChildren's Cancer Research Center and Department of PediatricsKlinikum rechts der IsarTechnische Universität MünchenComprehensive Cancer Center Munich (CCCM)German Translational Cancer Research Consortium (DKTK)MunichGermanyInstitute of PathologyHelmholtz Zentrum München ‐ German Research Centre for Environmental Health (GmbH)NeuherbergGermanyDepartment of Medicine IV, Hematology and OncologyUniversity Hospital HalleGermanyInstitute of PathologyHelmholtz Zentrum München ‐ German Research Centre for Environmental Health (GmbH)NeuherbergGermanyLaboratory for Functional Genomics and Transplantation BiologyChildren's Cancer Research Center and Department of PediatricsKlinikum rechts der IsarTechnische Universität MünchenComprehensive Cancer Center Munich (CCCM)German Translational Cancer Research Consortium (DKTK)MunichGermanyLaboratory for Functional Genomics and Transplantation BiologyChildren's Cancer Research Center and Department of PediatricsKlinikum rechts der IsarTechnische Universität MünchenComprehensive Cancer Center Munich (CCCM)German Translational Cancer Research Consortium (DKTK)MunichGermanyLaboratory for Functional Genomics and Transplantation BiologyChildren's Cancer Research Center and Department of PediatricsKlinikum rechts der IsarTechnische Universität MünchenComprehensive Cancer Center Munich (CCCM)German Translational Cancer Research Consortium (DKTK)MunichGermanyLaboratory for Functional Genomics and Transplantation BiologyChildren's Cancer Research Center and Department of PediatricsKlinikum rechts der IsarTechnische Universität MünchenComprehensive Cancer Center Munich (CCCM)German Translational Cancer Research Consortium (DKTK)MunichGermanyInstitute of PathologyUniversity DüsseldorfGermanyDepartment of Medicine IV, Hematology and OncologyUniversity Hospital HalleGermanyDepartment of Molecular OncologyBritish Columbia Cancer Research CentreVancouverBCCanadaLaboratory for Functional Genomics and Transplantation BiologyChildren's Cancer Research Center and Department of PediatricsKlinikum rechts der IsarTechnische Universität MünchenComprehensive Cancer Center Munich (CCCM)German Translational Cancer Research Consortium (DKTK)MunichGermanyLaboratory for Functional Genomics and Transplantation BiologyChildren's Cancer Research Center and Department of PediatricsKlinikum rechts der IsarTechnische Universität MünchenComprehensive Cancer Center Munich (CCCM)German Translational Cancer Research Consortium (DKTK)MunichGermanyEwing sarcomas (ES) are highly malignant, osteolytic bone or soft tissue tumors, which are characterized by EWS–ETS translocations and early metastasis to lung and bone. In this study, we investigated the role of the BRICHOS chaperone domain‐containing endochondral bone protein chondromodulin I (CHM1) in ES pathogenesis. CHM1 is significantly overexpressed in ES, and chromosome immunoprecipitation (ChIP) data demonstrate CHM1 to be directly bound by an EWS–ETS translocation, EWS‐FLI1. Using RNA interference, we observed that CHM1 promoted chondrogenic differentiation capacity of ES cells but decreased the expression of osteolytic genes such as HIF1A, IL6, JAG1, and VEGF. This was in line with the induction of the number of tartrate‐resistant acid phosphatase (TRAP+)‐stained osteoclasts in an orthotopic model of local tumor growth after CHM1 knockdown, indicating that CHM1‐mediated inhibition of osteomimicry might play a role in homing, colonization, and invasion into bone tissues. We further demonstrate that CHM1 enhanced the invasive potential of ES cells in vitro. This invasiveness was in part mediated via CHM1‐regulated matrix metallopeptidase 9 expression and correlated with the observation that, in an xenograft mouse model, CHM1 was essential for the establishment of lung metastases. This finding is in line with the observed increase in CHM1 expression in patient specimens with ES lung metastases. Our results suggest that CHM1 seems to have pleiotropic functions in ES, which need to be further investigated, but appears to be essential for the invasive and metastatic capacities of ES.https://doi.org/10.1002/1878-0261.12057CHM1endochondral boneEwing sarcomainvasionmetastasis |
| spellingShingle | Kristina vonHeyking Julia Calzada‐Wack Stefanie Göllner Frauke Neff Oxana Schmidt Tim Hensel David Schirmer Annette Fasan Irene Esposito Carsten Müller‐Tidow Poul H. Sorensen Stefan Burdach Günther H. S. Richter The endochondral bone protein CHM1 sustains an undifferentiated, invasive phenotype, promoting lung metastasis in Ewing sarcoma Molecular Oncology CHM1 endochondral bone Ewing sarcoma invasion metastasis |
| title | The endochondral bone protein CHM1 sustains an undifferentiated, invasive phenotype, promoting lung metastasis in Ewing sarcoma |
| title_full | The endochondral bone protein CHM1 sustains an undifferentiated, invasive phenotype, promoting lung metastasis in Ewing sarcoma |
| title_fullStr | The endochondral bone protein CHM1 sustains an undifferentiated, invasive phenotype, promoting lung metastasis in Ewing sarcoma |
| title_full_unstemmed | The endochondral bone protein CHM1 sustains an undifferentiated, invasive phenotype, promoting lung metastasis in Ewing sarcoma |
| title_short | The endochondral bone protein CHM1 sustains an undifferentiated, invasive phenotype, promoting lung metastasis in Ewing sarcoma |
| title_sort | endochondral bone protein chm1 sustains an undifferentiated invasive phenotype promoting lung metastasis in ewing sarcoma |
| topic | CHM1 endochondral bone Ewing sarcoma invasion metastasis |
| url | https://doi.org/10.1002/1878-0261.12057 |
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