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Title: A zebrafish embryo screen utilizing gastrulation identifies the HTR2C inhibitor pizotifen as a suppressor of EMT-mediated metastasis
Authors: Nakayama, Joji 
Tan, Lora 
Li, Yan 
Goh, Boon Cher 
Wang, Shu 
Makinoshima, Hideki
Gong, Zhiyuan 
Keywords: developmental biology
phenotyping screening
Issue Date: 17-Dec-2021
Publisher: NLM (Medline)
Citation: Nakayama, Joji, Tan, Lora, Li, Yan, Goh, Boon Cher, Wang, Shu, Makinoshima, Hideki, Gong, Zhiyuan (2021-12-17). A zebrafish embryo screen utilizing gastrulation identifies the HTR2C inhibitor pizotifen as a suppressor of EMT-mediated metastasis. eLife 10. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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 5 hr. The screen tested 1280 FDA-approved drugs and identified pizotifen, an antagonist for serotonin receptor 2C (HTR2C) as an epiboly-interrupting drug. Pharmacological 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 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. © 2021, Nakayama et al.
Source Title: eLife
ISSN: 2050-084X
DOI: 10.7554/elife.70151
Rights: Attribution 4.0 International
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