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Stem Cell Reports. 2019 Jan 8;12(1):122-134. doi: 10.1016/j.stemcr.2018.12.002.

A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs.

Author information

1
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
2
Small Molecules Drug Development Core Facility, Office of Research Administration, Case Western Reserve University, Cleveland, OH 44106, USA.
3
Department of Electrical Engineering and Computer Science, Center for Wireless Integrated MicroSensing and Systems (WIMS2), The University of Michigan, Ann Arbor, MI, USA.
4
Department of Genetics and Multiscale Biology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.
5
Department of Genetics and Genomic Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
6
Department of Medicine, Magee Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
7
Small Molecules Drug Development Core Facility, Office of Research Administration, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Genetics and Genomic Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
8
Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
9
Rogel Cancer Center, The University of Michigan, Michigan Medicine, Ann Arbor, MI, USA; Department of Obstetrics and Gynecology, The University of Michigan, Michigan Medicine, Ann Arbor, MI, USA; Department of Pathology, The University of Michigan, Michigan Medicine, Ann Arbor, MI, USA. Electronic address: adifeo@med.umich.edu.

Abstract

Tumor-initiating cells (TICs) contribute to drug resistance and tumor recurrence in cancers, thus experimental approaches to dissect the complexity of TICs are required to design successful TIC therapeutic strategies. Here, we show that miRNA-3' UTR sensor vectors can be used as a pathway-based method to identify, enrich, and analyze TICs from primary solid tumor patient samples. We have found that an miR-181ahigh subpopulation of cells sorted from primary ovarian tumor cells exhibited TIC properties in vivo, were enriched in response to continuous cisplatin treatment, and showed activation of numerous major stem cell regulatory pathways. This miRNA-sensor-based platform enabled high-throughput drug screening leading to identification of BET inhibitors as transcriptional inhibitors of miR-181a. Taken together, we provide a valuable miRNA-sensor-based approach to broaden the understanding of complex TIC regulatory mechanisms in cancers and to identify miRNA-targeting drugs.

KEYWORDS:

BET inhibitors; miR-181a; miRNA sensor; ovarian cancer; tumor heterogeneity; tumor-initiating cells

PMID:
30629937
DOI:
10.1016/j.stemcr.2018.12.002
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