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.
Highlights
Metastasis, a leading contributor to the morbidity of cancer patients, occurs through multiple steps: invasion, intravasation, extravasation, colonization, and metastatic tumor formation [1,2,3]
Before performing a screening assay, we validated a core of our concept through comparing the genes expressed in zebrafish gastrulation with the genes which expressed in epithelial to mesenchymal transition (EMT)-mediated metastasis
Elevated expression of protein arginine methyltransferase 1 (PRMT1) and CYP11A1 were observed in highly metastatic human breast cancer cell lines and knockdown of these genes through RNA interference suppressed the motility and invasion of MDA-MB-231 cells without affecting their viability (Figure 1-figure supplement 2A-C)
Summary
Metastasis, a leading contributor to the morbidity of cancer patients, occurs through multiple steps: invasion, intravasation, extravasation, colonization, and metastatic tumor formation [1,2,3]. The physical translocation of cancer cells is an initial step of metastasis and molecular mechanisms of it involve cell motility, the breakdown of local basement membrane, loss of cell polarity, acquisition of stem cell-like properties, and EMT [4, 5] These cell-biological phenomena are observed during vertebrate gastrulation in that evolutionarily conserved morphogenetic movements of epiboly, internalization, convergence, and extension progress [6]. HTR2C induced EMT and promoted metastatic dissemination of non-metastatic cancer cells in a zebrafish xenotransplantation model These results demonstrated that this concept could offer a novel high-throughput platform for discovery of anti-metastasis drugs and can be converted to a chemical genetic screening platform
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