The endochondral bone protein CHM 1 sustains an undifferentiated, invasive phenotype, promoting lung metastasis in Ewing sarcoma

• Published in: Molecular oncology Vol. 11; no. 9; pp. 1288 - 1301
• Main Authors: von Heyking, Kristina, Calzada‐Wack, Julia, Göllner, Stefanie, Neff, Frauke, Schmidt, Oxana, Hensel, Tim, Schirmer, David, Fasan, Annette, Esposito, Irene, Müller‐Tidow, Carsten, Sorensen, Poul H., Burdach, Stefan, Richter, Günther H. S.
• Format: Journal Article
• Language: English
• Published: 01-09-2017
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12057

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
1) in
ES
pathogenesis.
CHM
1 is significantly overexpressed in
ES
, and chromosome immunoprecipitation (Ch
IP
) data demonstrate
CHM
1 to be directly bound by an
EWS
–
ETS
translocation,
EWS
‐
FLI
1. Using
RNA
interference, we observed that
CHM
1 promoted chondrogenic differentiation capacity of
ES
cells but decreased the expression of osteolytic genes such as
HIF
1A
,
IL
6
,
JAG
1
, 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
CHM
1 knockdown, indicating that
CHM
1‐mediated inhibition of osteomimicry might play a role in homing, colonization, and invasion into bone tissues. We further demonstrate that
CHM
1 enhanced the invasive potential of
ES
cells
in vitro
. This invasiveness was in part mediated via
CHM
1‐regulated matrix metallopeptidase 9 expression and correlated with the observation that, in an xenograft mouse model,
CHM
1 was essential for the establishment of lung metastases. This finding is in line with the observed increase in
CHM
1 expression in patient specimens with
ES
lung metastases. Our results suggest that
CHM
1 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
.