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

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 meth...

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Autores principales: Belur Nagaraj, Anil, Joseph, Peronne, Ponting, Erin, Fedorov, Yuriy, Singh, Salendra, Cole, Alex, Lee, Woncheol, Yoon, Euisik, Baccarini, Alessia, Scacheri, Peter, Buckanovich, Ronald, Adams, Drew J., Drapkin, Ronny, Brown, Brian D., DiFeo, Analisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335585/
https://www.ncbi.nlm.nih.gov/pubmed/30629937
http://dx.doi.org/10.1016/j.stemcr.2018.12.002
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author Belur Nagaraj, Anil
Joseph, Peronne
Ponting, Erin
Fedorov, Yuriy
Singh, Salendra
Cole, Alex
Lee, Woncheol
Yoon, Euisik
Baccarini, Alessia
Scacheri, Peter
Buckanovich, Ronald
Adams, Drew J.
Drapkin, Ronny
Brown, Brian D.
DiFeo, Analisa
author_facet Belur Nagaraj, Anil
Joseph, Peronne
Ponting, Erin
Fedorov, Yuriy
Singh, Salendra
Cole, Alex
Lee, Woncheol
Yoon, Euisik
Baccarini, Alessia
Scacheri, Peter
Buckanovich, Ronald
Adams, Drew J.
Drapkin, Ronny
Brown, Brian D.
DiFeo, Analisa
author_sort Belur Nagaraj, Anil
collection PubMed
description 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.
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spelling pubmed-63355852019-01-22 A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs Belur Nagaraj, Anil Joseph, Peronne Ponting, Erin Fedorov, Yuriy Singh, Salendra Cole, Alex Lee, Woncheol Yoon, Euisik Baccarini, Alessia Scacheri, Peter Buckanovich, Ronald Adams, Drew J. Drapkin, Ronny Brown, Brian D. DiFeo, Analisa Stem Cell Reports Article 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. Elsevier 2019-01-08 /pmc/articles/PMC6335585/ /pubmed/30629937 http://dx.doi.org/10.1016/j.stemcr.2018.12.002 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Belur Nagaraj, Anil
Joseph, Peronne
Ponting, Erin
Fedorov, Yuriy
Singh, Salendra
Cole, Alex
Lee, Woncheol
Yoon, Euisik
Baccarini, Alessia
Scacheri, Peter
Buckanovich, Ronald
Adams, Drew J.
Drapkin, Ronny
Brown, Brian D.
DiFeo, Analisa
A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs
title A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs
title_full A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs
title_fullStr A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs
title_full_unstemmed A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs
title_short A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs
title_sort mirna-mediated approach to dissect the complexity of tumor-initiating cell function and identify mirna-targeting drugs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335585/
https://www.ncbi.nlm.nih.gov/pubmed/30629937
http://dx.doi.org/10.1016/j.stemcr.2018.12.002
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