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von Heyking, K.* ; Calzada-Wack, J. ; Göllner, S.* ; Neff, F. ; Schmidt, O.* ; Hensel, T.* ; Schirmer, D.* ; Fasan, A.* ; Esposito, I.* ; Müller-Tidow, C.* ; Sorensen, P.H.B.* ; Burdach, S.* ; Richter, G.H.*

The endochondral bone protein CHM1 sustains an undifferentiated, invasive phenotype, promoting lung metastasis in Ewing sarcoma.

Mol. Oncol. 11, 1288-1301 (2017)
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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 over-expressed 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 knock down, 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 MMP9 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, that need to be further investigated, but appears to be essential for the invasive and metastatic capacities of ES.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Chm1 ; Ewing Sarcoma ; Endochondral Bone ; Invasion ; Metastasis; Peripheral Neuroectodermal Tumors; Stem-cell Rescue; Chondromodulin-i; Molecular Pathogenesis; Genomic Landscape; Breast-cancer; Expression; Family; Gene; Differentiation
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 1574-7891
e-ISSN 1878-0261
Journal Molecular Oncology
Quellenangaben Volume: 11, Issue: 9, Pages: 1288-1301 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam [u.a.]
Reviewing status Peer reviewed
Institute(s) Institute of Pathology (PATH)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-500300-001
DOI 10.1002/1878-0261.12057
WOS ID WOS:000408847000012
Scopus ID 85020140509
PubMed ID 28319320
Erfassungsdatum 2017-03-23
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