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...

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Main Authors:	Komura, Shingo, Semi, Katsunori, Itakura, Fumiaki, Shibata, Hirofumi, Ohno, Takatoshi, Hotta, Akitsu, Woltjen, Knut, Yamamoto, Takuya, Akiyama, Haruhiko, Yamada, Yasuhiro
Format:	Online
Language:	English
Published:	Elsevier 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834047/

id	pubmed-4834047
recordtype	oai_dc
spelling	pubmed-48340472016-04-27 An EWS-FLI1-Induced Osteosarcoma Model Unveiled a Crucial Role of Impaired Osteogenic Differentiation on Osteosarcoma Development Komura, Shingo Semi, Katsunori Itakura, Fumiaki Shibata, Hirofumi Ohno, Takatoshi Hotta, Akitsu Woltjen, Knut Yamamoto, Takuya Akiyama, Haruhiko Yamada, Yasuhiro Article 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. Elsevier 2016-03-17 /pmc/articles/PMC4834047/ /pubmed/26997645 http://dx.doi.org/10.1016/j.stemcr.2016.02.009 Text en © 2016 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Komura, Shingo Semi, Katsunori Itakura, Fumiaki Shibata, Hirofumi Ohno, Takatoshi Hotta, Akitsu Woltjen, Knut Yamamoto, Takuya Akiyama, Haruhiko Yamada, Yasuhiro
spellingShingle	Komura, Shingo Semi, Katsunori Itakura, Fumiaki Shibata, Hirofumi Ohno, Takatoshi Hotta, Akitsu Woltjen, Knut Yamamoto, Takuya Akiyama, Haruhiko Yamada, Yasuhiro An EWS-FLI1-Induced Osteosarcoma Model Unveiled a Crucial Role of Impaired Osteogenic Differentiation on Osteosarcoma Development
author_facet	Komura, Shingo Semi, Katsunori Itakura, Fumiaki Shibata, Hirofumi Ohno, Takatoshi Hotta, Akitsu Woltjen, Knut Yamamoto, Takuya Akiyama, Haruhiko Yamada, Yasuhiro
author_sort	Komura, Shingo
title	An EWS-FLI1-Induced Osteosarcoma Model Unveiled a Crucial Role of Impaired Osteogenic Differentiation on Osteosarcoma Development
title_short	An EWS-FLI1-Induced Osteosarcoma Model Unveiled a Crucial Role of Impaired Osteogenic Differentiation on Osteosarcoma Development
title_full	An EWS-FLI1-Induced Osteosarcoma Model Unveiled a Crucial Role of Impaired Osteogenic Differentiation on Osteosarcoma Development
title_fullStr	An EWS-FLI1-Induced Osteosarcoma Model Unveiled a Crucial Role of Impaired Osteogenic Differentiation on Osteosarcoma Development
title_full_unstemmed	An EWS-FLI1-Induced Osteosarcoma Model Unveiled a Crucial Role of Impaired Osteogenic Differentiation on Osteosarcoma Development
title_sort	ews-fli1-induced osteosarcoma model unveiled a crucial role of impaired osteogenic differentiation on osteosarcoma development
description	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.
publisher	Elsevier
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834047/
_version_	1613567155905757184

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

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