title: Targeting cancer stem-like cells as an approach to defeating cellular heterogeneity in Ewing sarcoma.
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.
authors.affiliation: Experimental Pathology Service, CHUV and University of Lausanne, Lausanne, Switzerland.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cornaz-Buros
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nicolo
authors.initials: N
authors.lastname: Riggi
authors.affiliation: Department of Pathology, HUG and University of Geneva, Geneva, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: DeVito
authors.affiliation: Mouse Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Sarre
authors.affiliation: Clinical Pathology Service, CHUV and University of Lausanne, Lausanne, Switzerland.
authors.forename: Igor
authors.initials: I
authors.lastname: Letovanec
authors.affiliation: Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.affiliation: Experimental Pathology Service, CHUV and University of Lausanne, Lausanne, Switzerland. Ivan.Stamenkovic@chuv.ch.
authors.forename: Ivan
authors.initials: I
authors.lastname: Stamenkovic
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D015365:Enoxacin / Q000494:pharmacology; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010455:Peptides / Q000032:analysis; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D015365:Enoxacin; D004317:Doxorubicin