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

Anil Belur Nagaraj; Peronne Joseph; Erin Ponting; Yuriy Fedorov; Salendra Singh; Alex Cole; Woncheol Lee; Euisik Yoon; Alessia Baccarini; Peter Scacheri; Ronald Buckanovich; Drew J Adams; Ronny Drapkin; Brian D Brown; Analisa DiFeo

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

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

Authors

Affiliations

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-181a^high 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

3' Untranslated Regions
Antineoplastic Agents / pharmacology*
Biosensing Techniques / methods*
Cell Line, Tumor
Drug Discovery / methods*
Female
Humans
MicroRNAs / genetics*
MicroRNAs / metabolism
Neoplastic Stem Cells / drug effects*
Neoplastic Stem Cells / metabolism
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology

Substances

3' Untranslated Regions
Antineoplastic Agents
MicroRNAs

Abstract

Publication types

MeSH terms

Substances

Grants and funding