An EWS-FLI1-Induced Osteosarcoma Model Unveiled a Crucial Role of Impaired Osteogenic Differentiation on Osteosarcoma Development

EWS-FLI1, a multi-functional fusion oncogene, is exclusively detected in Ewing sarcomas. However, previous studies reported that rare varieties of osteosarcomas also harbor EWS-ETS family fusion. Here, using the doxycycline-inducible EWS-FLI1 system, we established an EWS-FLI1-dependent osteosarcoma model from murine bone marrow stromal cells. We revealed that the withdrawal of EWS-FLI1 expression enhances the osteogenic differentiation of sarcoma cells, leading to mature bone formation. Taking advantage of induced pluripotent stem cell (iPSC) technology, we also show that sarcoma-derived iPSCs with cancer-related genetic abnormalities exhibited an impaired differentiation program of osteogenic lineage irrespective of the EWS-FLI1 expression. Finally, we demonstrate that EWS-FLI1 contributed to secondary sarcoma development from the sarcoma iPSCs after osteogenic differentiation. These findings demonstrate that modulating cellular differentiation is a fundamental principle of EWS-FLI1-induced osteosarcoma development. This in vitro cancer model using sarcoma iPSCs should provide a unique platform for dissecting relationships between the cancer genome and cellular differentiation. [Display omitted] •EWS-FLI1 induces small-cell osteosarcoma from murine bone marrow stromal cells•EWS-FLI1 inhibits osteogenic differentiation of sarcoma cells in vivo•Modulating differentiation is a fundamental principle of osteosarcoma development•Sarcoma iPSCs should provide a unique platform for dissecting cancer biology In this article, Yamada and colleagues established a murine EWS-FLI1-induced osteosarcoma model using a doxycycline-inducible-EWS-FLI1 expression system. They showed that EWS-FLI1 expression inhibits the osteogenic differentiation of sarcoma cells in vitro and in vivo. By using sarcoma-derived iPSCs, they demonstrated that modulating cellular differentiation is a fundamental principle of EWS-FLI1-induced osteosarcoma development.