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 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 .