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

Abstract

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.

• Authors: Shingo Komura, Katsunori Semi, Fumiaki Itakura, Hirofumi Shibata, Takatoshi Ohno, Akitsu Hotta, Knut Woltjen, Takuya Yamamoto, Haruhiko Akiyama, Yasuhiro Yamada
• Journal: Stem cell reports (Stem Cell Reports) Vol. 6 Issue 4 Pg. 592-606 (Apr 12 2016) ISSN: 2213-6711 [Electronic] United States
• PMID: 26997645 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• EWS-FLI fusion protein
• Oncogene Proteins, Fusion
• Proto-Oncogene Protein c-fli-1
• RNA-Binding Protein EWS

Topics

• Animals
• Blotting, Western
• Bone Neoplasms (genetics, metabolism, pathology)
• Carcinogenesis (genetics, metabolism)
• Cell Differentiation (genetics)
• Cell Line, Tumor
• Cell Lineage (genetics)
• Cell Transformation, Neoplastic (genetics, metabolism)
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic
• Humans
• Induced Pluripotent Stem Cells (metabolism)
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• Mice, SCID
• Oncogene Proteins, Fusion (genetics, metabolism)
• Osteogenesis (genetics)
• Osteosarcoma (genetics, metabolism, pathology)
• Proto-Oncogene Protein c-fli-1 (genetics, metabolism)
• RNA-Binding Protein EWS (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Transplantation, Heterologous