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 (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.
Laboratory for Functional Genomics and Transplantation Biology, Children's Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Comprehensive Cancer Center Munich (CCCM), German Translational Cancer Research Consortium (DKTK), Munich, Germany.
Kristina
K
von Heyking
Institute of Pathology, Helmholtz Zentrum München - German Research Centre for Environmental Health (GmbH), Neuherberg, Germany.
Julia
J
Calzada-Wack
Department of Medicine IV, Hematology and Oncology, University Hospital Halle, Germany.
Stefanie
S
Göllner
Institute of Pathology, Helmholtz Zentrum München - German Research Centre for Environmental Health (GmbH), Neuherberg, Germany.
Frauke
F
Neff
Laboratory for Functional Genomics and Transplantation Biology, Children's Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Comprehensive Cancer Center Munich (CCCM), German Translational Cancer Research Consortium (DKTK), Munich, Germany.
Oxana
O
Schmidt
Laboratory for Functional Genomics and Transplantation Biology, Children's Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Comprehensive Cancer Center Munich (CCCM), German Translational Cancer Research Consortium (DKTK), Munich, Germany.
Tim
T
Hensel
Laboratory for Functional Genomics and Transplantation Biology, Children's Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Comprehensive Cancer Center Munich (CCCM), German Translational Cancer Research Consortium (DKTK), Munich, Germany.
David
D
Schirmer
Laboratory for Functional Genomics and Transplantation Biology, Children's Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Comprehensive Cancer Center Munich (CCCM), German Translational Cancer Research Consortium (DKTK), Munich, Germany.
Annette
A
Fasan
Institute of Pathology, University Düsseldorf, Germany.
Irene
I
Esposito
Department of Medicine IV, Hematology and Oncology, University Hospital Halle, Germany.|Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Germany.
Carsten
C
Müller-Tidow
Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
Poul H
PH
Sorensen
Laboratory for Functional Genomics and Transplantation Biology, Children's Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Comprehensive Cancer Center Munich (CCCM), German Translational Cancer Research Consortium (DKTK), Munich, Germany.
Stefan
S
Burdach
Laboratory for Functional Genomics and Transplantation Biology, Children's Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Comprehensive Cancer Center Munich (CCCM), German Translational Cancer Research Consortium (DKTK), Munich, Germany.
Günther H S
GHS
Richter
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D010641:Phenotype; D012512:Sarcoma, Ewing / Q000235:genetics / Q000473:pathology*
D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C068675:CNMD protein, human
CHM1; Ewing sarcoma; endochondral bone; invasion; metastasis