EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells
- Nicolò Riggi1,5,
- Mario-Luca Suvà1,5,
- Claudio De Vito1,
- Paolo Provero2,
- Jean-Christophe Stehle1,
- Karine Baumer1,
- Luisa Cironi1,
- Michalina Janiszewska1,
- Tanja Petricevic1,
- Domizio Suvà3,
- Stéphane Tercier4,
- Jean-Marc Joseph4,
- Louis Guillou1 and
- Ivan Stamenkovic1,6
- 1Division of Experimental Pathology, Institute of Pathology, University of Lausanne, Lausanne CH-1011, Switzerland;
- 2Department of Genetics Biology and Biochemistry, University of Turin, Turin 10126, Italy;
- 3Department of Orthopedics, University of Geneva, Geneva CH-1211, Switzerland;
- 4Department of Pediatric Surgery, University of Lausanne, Lausanne CH-1011, Switzerland
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↵5 These authors contributed equally to this work.
Abstract
Cancer stem cells (CSCs) display plasticity and self-renewal properties reminiscent of normal tissue stem cells, but the events responsible for their emergence remain obscure. We recently identified CSCs in Ewing sarcoma family tumors (ESFTs) and showed that they retain mesenchymal stem cell (MSC) plasticity. In the present study, we addressed the mechanisms that underlie ESFT CSC development. We show that the EWS-FLI-1 fusion gene, associated with 85%–90% of ESFTs and believed to initiate their pathogenesis, induces expression of the embryonic stem cell (ESC) genes OCT4, SOX2, and NANOG in human pediatric MSCs (hpMSCs) but not in their adult counterparts. Moreover, under appropriate culture conditions, hpMSCs expressing EWS-FLI-1 generate a cell subpopulation displaying ESFT CSC features in vitro. We further demonstrate that induction of the ESFT CSC phenotype is the result of the combined effect of EWS-FLI-1 on its target gene expression and repression of microRNA-145 (miRNA145) promoter activity. Finally, we provide evidence that EWS-FLI-1 and miRNA-145 function in a mutually repressive feedback loop and identify their common target gene, SOX2, in addition to miRNA145 itself, as key players in ESFT cell differentiation and tumorigenicity. Our observations provide insight for the first time into the mechanisms whereby a single oncogene can reprogram primary cells to display a CSC phenotype.
Keywords
Footnotes
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↵6 Corresponding author.
E-MAIL Ivan.Stamenkovic{at}chuv.ch; FAX 41--21-314-7110.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1899710.
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Supplemental material is available at http://www.genesdev.org.
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- Received December 24, 2009.
- Accepted March 5, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press