PUBLICATION
A chemical screen based on an interruption of zebrafish gastrulation identifies the HTR2C inhibitor Pizotifen as a suppressor of EMT-mediated metastasis
- Authors
- Nakayama, J., Tan, L., Li, Y., Goh, B.C., Wang, S., Makinoshima, H., Gong, Z.
- ID
- ZDB-PUB-211221-10
- Date
- 2021
- Source
- eLIFE 10: (Journal)
- Registered Authors
- Gong, Zhiyuan
- Keywords
- developmental biology, zebrafish
- MeSH Terms
-
- Animals
- Cell Movement/drug effects*
- Drug Discovery
- Embryo, Nonmammalian/drug effects*
- Epithelial-Mesenchymal Transition*
- Female
- Gastrulation/drug effects*
- High-Throughput Screening Assays/methods*
- Humans
- Mice, Inbred BALB C
- Neoplasm Metastasis/drug therapy
- Neoplasm Metastasis/prevention & control
- Pizotyline/pharmacology*
- Receptor, Serotonin, 5-HT2C/genetics*
- Serotonin 5-HT2 Receptor Antagonists/pharmacology*
- Signal Transduction/drug effects
- Small Molecule Libraries/pharmacology
- Transplantation, Heterologous
- Zebrafish
- Zebrafish Proteins/genetics
- PubMed
- 34919051 Full text @ Elife
Citation
Nakayama, J., Tan, L., Li, Y., Goh, B.C., Wang, S., Makinoshima, H., Gong, Z. (2021) A chemical screen based on an interruption of zebrafish gastrulation identifies the HTR2C inhibitor Pizotifen as a suppressor of EMT-mediated metastasis. eLIFE. 10:.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping