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Therapeutics, Targets, and Chemical Biology

Targeting Cancer Stem–like Cells as an Approach to Defeating Cellular Heterogeneity in Ewing Sarcoma

Sandrine Cornaz-Buros, Nicolo Riggi, Claudio DeVito, Alexandre Sarre, Igor Letovanec, Paolo Provero and Ivan Stamenkovic
Sandrine Cornaz-Buros
1Experimental Pathology Service, CHUV and University of Lausanne, Lausanne, Switzerland.
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Nicolo Riggi
2Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Claudio DeVito
3Department of Pathology, HUG and University of Geneva, Geneva, Switzerland.
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Alexandre Sarre
4Mouse Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland.
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Igor Letovanec
5Clinical Pathology Service, CHUV and University of Lausanne, Lausanne, Switzerland.
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Paolo Provero
6Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
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Ivan Stamenkovic
1Experimental Pathology Service, CHUV and University of Lausanne, Lausanne, Switzerland.
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  • For correspondence: Ivan.Stamenkovic@chuv.ch
DOI: 10.1158/0008-5472.CAN-14-1106 Published November 2014
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Abstract

Plasticity in cancer stem–like cells (CSC) may provide a key basis for cancer heterogeneity and therapeutic response. In this study, we assessed the effect of combining a drug that abrogates CSC properties with standard-of-care therapy in a Ewing sarcoma family tumor (ESFT). Emergence of CSC in this setting has been shown to arise from a defect in TARBP2-dependent microRNA maturation, which can be corrected by exposure to the fluoroquinolone enoxacin. In the present work, primary ESFT from four patients containing CD133+ CSC subpopulations ranging from 3% to 17% of total tumor cells were subjected to treatment with enoxacin, doxorubicin, or both drugs. Primary ESFT CSC and bulk tumor cells displayed divergent responses to standard-of-care chemotherapy and enoxacin. Doxorubicin, which targets the tumor bulk, displayed toxicity toward primary adherent ESFT cells in culture but not to CSC-enriched ESFT spheres. Conversely, enoxacin, which enhances miRNA maturation by stimulating TARBP2 function, induced apoptosis but only in ESFT spheres. In combination, the two drugs markedly depleted CSCs and strongly reduced primary ESFTs in xenograft assays. Our results identify a potentially attractive therapeutic strategy for ESFT that combines mechanism-based targeting of CSC using a low-toxicity antibiotic with a standard-of-care cytotoxic drug, offering immediate applications for clinical evaluation. Cancer Res; 74(22); 6610–22. ©2014 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received April 17, 2014.
  • Revision received August 20, 2014.
  • Accepted September 2, 2014.
  • ©2014 American Association for Cancer Research.
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Cancer Research: 74 (22)
November 2014
Volume 74, Issue 22
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Targeting Cancer Stem–like Cells as an Approach to Defeating Cellular Heterogeneity in Ewing Sarcoma
Sandrine Cornaz-Buros, Nicolo Riggi, Claudio DeVito, Alexandre Sarre, Igor Letovanec, Paolo Provero and Ivan Stamenkovic
Cancer Res November 15 2014 (74) (22) 6610-6622; DOI: 10.1158/0008-5472.CAN-14-1106

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Targeting Cancer Stem–like Cells as an Approach to Defeating Cellular Heterogeneity in Ewing Sarcoma
Sandrine Cornaz-Buros, Nicolo Riggi, Claudio DeVito, Alexandre Sarre, Igor Letovanec, Paolo Provero and Ivan Stamenkovic
Cancer Res November 15 2014 (74) (22) 6610-6622; DOI: 10.1158/0008-5472.CAN-14-1106
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