Journal Article 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

6 ( 4 )  , pp.592 - 606 , 2016-04-12 , Elsevier Inc.
iPS細胞を用いた新たな腫瘍モデルにより、肉腫形成メカニズムの一端を解明. 京都大学プレスリリース. 2016-03-18.
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.

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