title: 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.affiliation: Laboratory of Stem Cell Oncology, Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Komura
authors.affiliation: Laboratory of Stem Cell Oncology, Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Semi
authors.affiliation: Laboratory of Stem Cell Oncology, Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Itakura
authors.affiliation: Laboratory of Stem Cell Oncology, Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Shibata
authors.affiliation: Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Ohno
authors.affiliation: Laboratory of Stem Cell Oncology, Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Akitsu
authors.initials: A
authors.lastname: Hotta
authors.affiliation: Laboratory of Stem Cell Oncology, Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Knut
authors.initials: K
authors.lastname: Woltjen
authors.affiliation: Laboratory of Stem Cell Oncology, Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507, Japan; AMED-CREST, AMED 1-7-1 Otemach, Chiyodaku, Tokyo 100-0004, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Laboratory of Stem Cell Oncology, Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507, Japan. Electronic address: y-yamada@cira.kyoto-u.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics* / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS