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Cancer Therapy: Preclinical

The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis

Michael D. Deel, Katherine K. Slemmons, Ashley R. Hinson, Katia C. Genadry, Breanne A. Burgess, Lisa E.S. Crose, Nina Kuprasertkul, Kristianne M. Oristian, Rex C. Bentley and Corinne M. Linardic
Michael D. Deel
Division of Hematology-Oncology, Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina.
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Katherine K. Slemmons
Department of Pharmacology & Cancer Biology, School of Medicine, Duke University, Durham, North Carolina.
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Ashley R. Hinson
Division of Hematology-Oncology, Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina.
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Katia C. Genadry
Division of Hematology-Oncology, Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina.
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Breanne A. Burgess
Division of Hematology-Oncology, Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina.
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Lisa E.S. Crose
Division of Hematology-Oncology, Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina.
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Nina Kuprasertkul
Duke University, Durham, North Carolina.
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Kristianne M. Oristian
Division of Hematology-Oncology, Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina.
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Rex C. Bentley
Department of Pathology, School of Medicine, Duke University, Durham, North Carolina.
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Corinne M. Linardic
Division of Hematology-Oncology, Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina.Department of Pharmacology & Cancer Biology, School of Medicine, Duke University, Durham, North Carolina.
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  • For correspondence: linar001@mc.duke.edu
DOI: 10.1158/1078-0432.CCR-17-1207
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Abstract

Purpose: Alveolar rhabdomyosarcoma (aRMS) is a childhood soft tissue sarcoma driven by the signature PAX3-FOXO1 (P3F) fusion gene. Five-year survival for aRMS is <50%, with no improvement in over 4 decades. Although the transcriptional coactivator TAZ is oncogenic in carcinomas, the role of TAZ in sarcomas is poorly understood. The aim of this study was to investigate the role of TAZ in P3F-aRMS tumorigenesis.

Experimental Design: After determining from publicly available datasets that TAZ is upregulated in human aRMS transcriptomes, we evaluated whether TAZ is also upregulated in our myoblast-based model of P3F-initiated tumorigenesis, and performed IHC staining of 63 human aRMS samples from tissue microarrays. Using constitutive and inducible RNAi, we examined the impact of TAZ loss of function on aRMS oncogenic phenotypes in vitro and tumorigenesis in vivo. Finally, we performed pharmacologic studies in aRMS cell lines using porphyrin compounds, which interfere with TAZ-TEAD transcriptional activity.

Results: TAZ is upregulated in our P3F-initiated aRMS model, and aRMS cells and tumors have high nuclear TAZ expression. In vitro, TAZ suppression inhibits aRMS cell proliferation, induces apoptosis, supports myogenic differentiation, and reduces aRMS cell stemness. TAZ-deficient aRMS cells are enriched in G2–M phase of the cell cycle. In vivo, TAZ suppression attenuates aRMS xenograft tumor growth. Preclinical studies show decreased aRMS xenograft tumor growth with porphyrin compounds alone and in combination with vincristine.

Conclusions: TAZ is oncogenic in aRMS sarcomagenesis. While P3F is currently not therapeutically tractable, targeting TAZ could be a promising novel approach in aRMS. Clin Cancer Res; 1–15. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received May 3, 2017.
  • Revision received December 8, 2017.
  • Accepted March 2, 2018.
  • Published first March 7, 2018.
  • ©2018 American Association for Cancer Research.

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Published OnlineFirst April 13, 2018
doi: 10.1158/1078-0432.CCR-17-1207

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The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis
Michael D. Deel, Katherine K. Slemmons, Ashley R. Hinson, Katia C. Genadry, Breanne A. Burgess, Lisa E.S. Crose, Nina Kuprasertkul, Kristianne M. Oristian, Rex C. Bentley and Corinne M. Linardic
Clin Cancer Res April 13 2018 DOI: 10.1158/1078-0432.CCR-17-1207

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The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis
Michael D. Deel, Katherine K. Slemmons, Ashley R. Hinson, Katia C. Genadry, Breanne A. Burgess, Lisa E.S. Crose, Nina Kuprasertkul, Kristianne M. Oristian, Rex C. Bentley and Corinne M. Linardic
Clin Cancer Res April 13 2018 DOI: 10.1158/1078-0432.CCR-17-1207
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Clinical Cancer Research
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