A TARBP2-Dependent miRNA Expression Profile Underlies Cancer Stem Cell Properties and Provides Candidate Therapeutic Reagents in Ewing Sarcoma

SummaryWe have recently demonstrated that human pediatric mesenchymal stem cells can be reprogrammed toward a Ewing sarcoma family tumor (ESFT) cancer stem cell (CSC) phenotype by mechanisms that implicate microRNAs (miRNAs). Here, we show that the miRNA profile of ESFT CSCs is shared by embryonic stem cells and CSCs from divergent tumor types. We also provide evidence that the miRNA profile of ESFT CSCs is the result of reversible disruption of TARBP2-dependent miRNA maturation. Restoration of TARBP2 activity and systemic delivery of synthetic forms of either of two of its targets, miRNA-143 or miRNA-145, inhibited ESFT CSC clonogenicity and tumor growth in vivo. Our observations suggest that CSC self-renewal and tumor maintenance may depend on deregulation of TARBP2-dependent miRNA expression.

► Ewing sarcoma (ESFT) CSCs share a microRNA profile with CSCs from divergent tumors ► The microRNA profile in ESFT CSCs results from disruption of miRNA maturation ► miRNA maturation disruption in ESFT CSCs is due to reversible repression of TARBP2 ► Delivery of TARBP2-dependent miRNA143-145 cluster blocks ESFT growth