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Molecular Cancer Research
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Cancer Genes and Networks

The YAP1 Signaling Inhibitors, Verteporfin and CA3, Suppress the Mesothelioma Cancer Stem Cell Phenotype

Sivaveera Kandasamy, Gautam Adhikary, Ellen A. Rorke, Joseph S. Friedberg, McKayla B. Mickle, H. Richard Alexander and Richard L. Eckert
Sivaveera Kandasamy
1Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland.
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Gautam Adhikary
2Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
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Ellen A. Rorke
3Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland.
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Joseph S. Friedberg
1Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland.
4Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.
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McKayla B. Mickle
2Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
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H. Richard Alexander
5Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.
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Richard L. Eckert
2Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
4Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.
6Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland.
7Department of Reproductive Biology, University of Maryland School of Medicine, Baltimore, Maryland.
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  • For correspondence: reckert@umaryland.edu
DOI: 10.1158/1541-7786.MCR-19-0914 Published March 2020
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Abstract

Mesothelioma is an aggressive cancer that has a poor prognosis. Tumors develop in the mesothelial lining of the pleural and peritoneal cavities in response to asbestos exposure. Surgical debulking followed by chemotherapy is initially effective, but this treatment ultimately selects for resistant cells that form aggressive and therapy-resistant recurrent tumors. Mesothelioma cancer stem cells (MCS) are a highly aggressive subpopulation present in these tumors that are responsible for tumor maintenance and drug resistance. In this article, we examine the impact of targeting YAP1/TAZ/TEAD signaling in MCS cells. YAP1, TAZ, and TEADs are transcriptional mediators of the Hippo signaling cascade that activate gene expression to drive tumor formation. We show that two YAP1 signaling inhibitors, verteporfin and CA3, attenuate the MCS cell phenotype. Verteporfin or CA3 treatment reduces YAP1/TEAD level/activity to suppress MCS cell spheroid formation, Matrigel invasion, migration, and tumor formation. These agents also increase MCS cell apoptosis. Moreover, constitutively active YAP1 expression antagonizes inhibitor action, suggesting that loss of YAP1/TAZ/TEAD signaling is required for response to verteporfin and CA3. These agents are active against mesothelioma cells derived from peritoneal (epithelioid) and patient-derived pleural (sarcomatoid) mesothelioma, suggesting that targeting YAP1/TEAD signaling may be a useful treatment strategy.

Implications: These studies suggest that inhibition of YAP1 signaling may be a viable approach to treating mesothelioma.

This article is featured in Highlights of This Issue, p. 341

Footnotes

  • Mol Cancer Res 2020;18:343–51

  • Received September 5, 2019.
  • Revision received October 15, 2019.
  • Accepted November 12, 2019.
  • Published first November 15, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Research: 18 (3)
March 2020
Volume 18, Issue 3
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The YAP1 Signaling Inhibitors, Verteporfin and CA3, Suppress the Mesothelioma Cancer Stem Cell Phenotype
Sivaveera Kandasamy, Gautam Adhikary, Ellen A. Rorke, Joseph S. Friedberg, McKayla B. Mickle, H. Richard Alexander and Richard L. Eckert
Mol Cancer Res March 1 2020 (18) (3) 343-351; DOI: 10.1158/1541-7786.MCR-19-0914

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The YAP1 Signaling Inhibitors, Verteporfin and CA3, Suppress the Mesothelioma Cancer Stem Cell Phenotype
Sivaveera Kandasamy, Gautam Adhikary, Ellen A. Rorke, Joseph S. Friedberg, McKayla B. Mickle, H. Richard Alexander and Richard L. Eckert
Mol Cancer Res March 1 2020 (18) (3) 343-351; DOI: 10.1158/1541-7786.MCR-19-0914
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Molecular Cancer Research
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