1. Developmental Biology
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A chemical screen based on an interruption of zebrafish gastrulation identifies the HTR2C inhibitor Pizotifen as a suppressor of EMT-mediated metastasis

  1. Joji Nakayama  Is a corresponding author
  2. Lora Tan
  3. Yan Li
  4. Boon Cher Goh
  5. Shu Wang
  6. Hideki Makinoshima
  7. Zhiyuan Gong  Is a corresponding author
  1. National University of Singapore, Singapore
  2. National Cancer Center, Japan
Research Article
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Cite this article as: eLife 2021;10:e70151 doi: 10.7554/eLife.70151

Abstract

Metastasis is responsible for approximately 90% of cancer-associated mortality but few models exist that allow for rapid and effective screening of anti-metastasis drugs. Current mouse models of metastasis are too expensive and time consuming to use for rapid and high-throughput screening. Therefore, we created a unique screening concept utilizing conserved mechanisms between zebrafish gastrulation and cancer metastasis for identification of potential anti-metastatic drugs. We hypothesized that small chemicals that interrupt zebrafish gastrulation might also suppress metastatic progression of cancer cells and developed a phenotype-based chemical screen to test the hypothesis. The screen used epiboly, the first morphogenetic movement in gastrulation, as a marker and enabled 100 chemicals to be tested in five hours. The screen tested 1280 FDA-approved drugs and identified Pizotifen, an antagonist for serotonin receptor 2C (HTR2C) as an epiboly-interrupting drug. Pharmacologic and genetic inhibition of HTR2C suppressed metastatic progression in a mouse model. Blocking HTR2C with Pizotifen restored epithelial properties to metastatic cells through inhibition of Wnt-signaling. In contrast, HTR2C induced epithelial to mesenchymal transition (EMT) through activation of Wnt-signaling and promoted metastatic dissemination of human cancer cells in a zebrafish xenotransplantation model. Taken together, our concept offers a novel platform for discovery of anti-metastasis drugs.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Joji Nakayama

    Department of Biological Science, National University of Singapore, Singapore, Singapore
    For correspondence
    zmetastasis@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1077-140X
  2. Lora Tan

    Department of Biological Science, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  3. Yan Li

    Department of Biological Science, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  4. Boon Cher Goh

    Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Shu Wang

    Department of Biological Science, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  6. Hideki Makinoshima

    Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Zhiyuan Gong

    Department of Biological Science, National University of Singapore, Singapore, Singapore
    For correspondence
    dbsgzy@nus.edu.sg
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Medical Research Council (R-154000547511)

  • Zhiyuan Gong

Ministry of Education - Singapore (R-154000A23112)

  • Zhiyuan Gong

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The study protocol using zebrafish was approved by the Institutional Animal Care and Use Committee of the National University of Singapore (protocol number: R16-1068). The study protocol using mice (protocol number: BRC IACUC #110612) was approved by A*STAR (Agency for Science, Technology and Research, Singapore).

Reviewing Editor

  1. Yasuhito Shimada

Publication history

  1. Preprint posted: March 5, 2021 (view preprint)
  2. Received: May 7, 2021
  3. Accepted: December 17, 2021
  4. Accepted Manuscript published: December 17, 2021 (version 1)

Copyright

© 2021, Nakayama et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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