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

eLife

Boon Cher Goh¹  Lora Tan²  Zhiyuan Gong²  Yan Li²  Joji Nakayama³  Shu Wang⁴  Hideki Makinoshima⁵ 

[1] Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore;Department of Biological Science, National University of Singapore, Singapore, Singapore;Department of Biological Science, National University of Singapore, Singapore, Singapore;Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore;Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan;Shonai Regional Industry Promotion Center, Tsuruoka, Japan;Department of Biological Science, National University of Singapore, Singapore, Singapore;Institute of Bioengineering and Nanotechnology, Singapore, Singapore;Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan;Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan;

关键词: metastasis;    gastrulation;    EMT;    phenotyping screening;    mice;    serotonin;    Zebrafish;   

DOI  :  10.7554/eLife.70151

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY