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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Cancer Biology and Translational Studies

Functional miRNA Screening Identifies Wide-ranging Antitumor Properties of miR-3622b-5p and Reveals a New Therapeutic Combination Strategy in Ovarian Tumor Organoids

Mégane Vernon, Bernard Lambert, Matthieu Meryet-Figuière, Emilie Brotin, Louis-Bastien Weiswald, Hippolyte Paysant, Nicolas Vigneron, Anaïs Wambecke, Edwige Abeilard, Florence Giffard, Marie-Hélène Louis, Cécile Blanc-Fournier, Pascal Gauduchon, Laurent Poulain and Christophe Denoyelle
Mégane Vernon
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
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  • ORCID record for Mégane Vernon
Bernard Lambert
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
3CNRS, Normandy Regional Delegation, Caen, France.
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Matthieu Meryet-Figuière
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
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Emilie Brotin
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
4ImpedanCELL core facility, Federative Structure 4206 ICORE, UNICAEN, Caen, France.
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Louis-Bastien Weiswald
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
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Hippolyte Paysant
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
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  • ORCID record for Hippolyte Paysant
Nicolas Vigneron
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
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Anaïs Wambecke
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
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Edwige Abeilard
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
4ImpedanCELL core facility, Federative Structure 4206 ICORE, UNICAEN, Caen, France.
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Florence Giffard
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
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Marie-Hélène Louis
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
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Cécile Blanc-Fournier
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
5Biopathology Department, UNICANCER, Cancer Center F. Baclesse, Caen, France.
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Pascal Gauduchon
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
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Laurent Poulain
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
4ImpedanCELL core facility, Federative Structure 4206 ICORE, UNICAEN, Caen, France.
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Christophe Denoyelle
1Normandie Univ, UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for the Prevention and Treatment of Cancer), Biology and Innovative Therapies of Ovarian Cancers (BioTICLA), Caen, France.
2UNICANCER, Cancer Center François Baclesse, Caen, France.
4ImpedanCELL core facility, Federative Structure 4206 ICORE, UNICAEN, Caen, France.
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  • ORCID record for Christophe Denoyelle
  • For correspondence: c.denoyelle@baclesse.unicancer.fr
DOI: 10.1158/1535-7163.MCT-19-0510 Published July 2020
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Abstract

Novel therapeutic strategies are urgently required for the clinical management of chemoresistant ovarian carcinoma, which is the most lethal of the gynecologic malignancies. miRNAs hold promise because they play a critical role in determining the cell phenotype by regulating several hundreds of targets, which could constitute vulnerabilities of cancer cells. A combination of gain-of-function miRNA screening and real-time continuous cell monitoring allows the identification of miRNAs with robust cytotoxic effects in chemoresistant ovarian cancer cells. Focusing on miR-3622b-5p, we show that it induces apoptosis in several ovarian cancer cell lines by both directly targeting Bcl-xL and EGFR-mediating BIM upregulation. miR-3622b-5p also sensitizes cells to cisplatin by inhibiting Bcl-xL in ovarian cancer cell lines escaping BIM induction. miR-3622b-5p also exerts antimigratory capacities by targeting both LIMK1 and NOTCH1. These wide-ranging antitumor properties of miR-3622b-5p in ovarian cancer cells are mimicked by the associations of pharmacologic inhibitors targeting these proteins. The combination of an EGFR inhibitor together with a BH3-mimetic molecule induced a large decrease in cell viability in a panel of ovarian cancer cell lines and several ovarian patient-derived tumor organoids, suggesting the value of pursuing such a combination therapy in ovarian carcinoma. Altogether, our work highlights the potential of phenotype-based miRNA screening approaches to identify lethal interactions which might lead to new drug combinations and clinically applicable strategies.

This article is featured in Highlights of This Issue, p. 1383

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:1506–19

  • Received May 14, 2019.
  • Revision received November 20, 2019.
  • Accepted May 1, 2020.
  • Published first May 5, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (7)
July 2020
Volume 19, Issue 7
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Functional miRNA Screening Identifies Wide-ranging Antitumor Properties of miR-3622b-5p and Reveals a New Therapeutic Combination Strategy in Ovarian Tumor Organoids
Mégane Vernon, Bernard Lambert, Matthieu Meryet-Figuière, Emilie Brotin, Louis-Bastien Weiswald, Hippolyte Paysant, Nicolas Vigneron, Anaïs Wambecke, Edwige Abeilard, Florence Giffard, Marie-Hélène Louis, Cécile Blanc-Fournier, Pascal Gauduchon, Laurent Poulain and Christophe Denoyelle
Mol Cancer Ther July 1 2020 (19) (7) 1506-1519; DOI: 10.1158/1535-7163.MCT-19-0510

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Functional miRNA Screening Identifies Wide-ranging Antitumor Properties of miR-3622b-5p and Reveals a New Therapeutic Combination Strategy in Ovarian Tumor Organoids
Mégane Vernon, Bernard Lambert, Matthieu Meryet-Figuière, Emilie Brotin, Louis-Bastien Weiswald, Hippolyte Paysant, Nicolas Vigneron, Anaïs Wambecke, Edwige Abeilard, Florence Giffard, Marie-Hélène Louis, Cécile Blanc-Fournier, Pascal Gauduchon, Laurent Poulain and Christophe Denoyelle
Mol Cancer Ther July 1 2020 (19) (7) 1506-1519; DOI: 10.1158/1535-7163.MCT-19-0510
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Molecular Cancer Therapeutics
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