A zebrafish embryo screen utilizing gastrulation identifies the HTR2C inhibitor pizotifen as a suppressor of EMT-mediated metastasis

• Published in: eLife 2021-12, Vol.10
• Main Authors: Nakayama, Joji, Tan, Lora, Li, Yan, Goh, Boon Cher, Wang, Shu, Makinoshima, Hideki, Gong, Zhiyuan
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Cancer; Cell Movement - drug effects; Danio rerio; Developmental Biology; Drug Discovery; Drug screening; Drugs; Embryo, Nonmammalian - drug effects; Embryos; EMT; Epithelial-Mesenchymal Transition; Female; Gastrulation; Gastrulation - drug effects; High-throughput screening; High-Throughput Screening Assays - methods; Humans; Hypotheses; Mesenchyme; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Motility; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - prevention & control; Phenotypes; phenotyping screening; Pizotyline - pharmacology; Receptor, Serotonin, 5-HT2C - genetics; serotonin; Serotonin 5-HT2 Receptor Antagonists - pharmacology; Signal Transduction - drug effects; Small Molecule Libraries - pharmacology; Transplantation, Heterologous; Wnt protein; Xenografts; Zebrafish; Zebrafish Proteins - genetics
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.70151

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.