Abstract 3819: DKK2 mediates osteolysis, invasiveness and metastatic spread in Ewing sarcoma.

Abstract

Abstract Ewing sarcomas (ES) are malignant osteolytic bone and soft tissue tumors mostly affecting children and young adults, and are characterized by early lung and distant bone metastases. Here we identified the dickkopf 2 homolog (DKK2) as a highly over-expressed gene in ES, compared to normal tissues. DKK family members are increasingly recognized to be deregulated in bone metastasis. Using RNA interference, we show that DKK2 promotes anchorage-independent colony formation and proliferation of ES cells in vitro and tumorigenicity in vivo. Analysis of the invasion potential in vitro and in an orthotopic xenotransplantation model revealed a strong correlation of DKK2 expression and ES invasiveness that is possibly mediated by its downstream effector matrix metalloproteinase 1 (MMP1). Gene expression analyses proved DKK2 to differentially regulate genes such as CXCR4, PTHrP, RUNX2 and TGFβ1, that are associated with homing, invasion and growth of cancer cells in bone tissue as well as genes important for osteolysis, like HIF1α, JAG1, IL6 and VEGF. Moreover, we observed that DKK2 promotes bone infiltration and osteolysis in vivo, identifying DKK2 as a key factor for osteotropic malignancy. Interestingly, suppression of DKK2 expression increases neuronal differentiation, but at the same time decreases chondrogenic and osteogenic differentiation potential of ES cells. These data provide evidence that DKK2 is a key player in ES invasiveness and osteolysis, validating a critical role of DKK2 for malignancy and the differential phenotype of ES. Findings further suggest a broadly important role for a member of a family of antagonists of the Wnt pathway in driving bone invasion and osteolysis with potential implications for bone invasion in cancer generally. Citation Format: Günther H. Richter, Stefan Burdach, Kristina Hauer. DKK2 mediates osteolysis, invasiveness and metastatic spread in Ewing sarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3819. doi:10.1158/1538-7445.AM2013-3819