Abstract 3973: BRICHOS genes CHM1 and ITM2A maintain an undifferentiated, invasive phenotype in Ewing sarcoma

Abstract

Abstract Ewing sarcomas (ES) are highly malignant, osteolytic bone or soft tissue tumors, which are characterized by ews/ets translocations and early metastasis into lung and bone. In this study, we analyzed the role of the BRICHOS domain-containing genes CHM1 and ITM2A in ES pathogenesis, especially in bone-associated tumor growth and metastasis. Both genes are overexpressed in ES and among others appear to be important for chondrogenic differentiation. CHM1 in addition seems directly up-regulated by EWS/FLI1. Using RNA interference, we demonstrate that CHM1 and ITM2A slightly reduced bone invasiveness and osteolysis in vivo that is likely mediated by the suppression of the osteolytic genes HIF1α, IL6, JAG1 and VEGF. Furthermore, CHM1 and ITM2A suppressed the chondrogenic and to a lesser extend the osteogenic differentiation status of ES cells indicating that osteomimicry might play a role in homing, colonizing and invasion into bone tissues. Additionally, we show that both BRICHOS domain-containing genes significantly increased the expression of the stem cell genes, ABCG2 and PROM1. Together with the observed undifferentiated phenotype of ES cells, we demonstrate that CHM1 and ITM2A clearly enhanced lung metastasis in a xenograft mouse model in vivo. Our results suggest that CHM1 and ITM2A are essential players with respect to the undifferentiated phenotype and the metastatic behavior of ES cells. Citation Format: Kristina von Heyking, Annette Fasan, Stefan Burdach, Günther H. Richter. BRICHOS genes CHM1 and ITM2A maintain an undifferentiated, invasive phenotype in Ewing sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3973. doi:10.1158/1538-7445.AM2014-3973