A Novel Zebrafish Model of Metastasis Identifies the HSD11β1 Inhibitor Adrenosterone as a Suppressor of Epithelial-Mesenchymal Transition and Metastatic Dissemination

  • Mol Cancer Res. 2020 Mar;18(3):477-487. doi: 10.1158/1541-7786.MCR-19-0759.
Joji Nakayama  1  2  3 ,  Jeng-Wei Lu  4 ,  Hideki Makinoshima  2  5 ,  Zhiyuan Gong  1
Affiliations
  • 1. Department of Biological Sciences, National University of Singapore, Singapore. [email protected] [email protected].
  • 2. Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan.
  • 3. Shonai Regional Industry Promotion Center, Tsuruoka, Japan.
  • 4. Department of Biological Sciences, National University of Singapore, Singapore.
  • 5. Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
PMID: 31748280 DOI: 10.1158/1541-7786.MCR-19-0759
Abstract

Metastasis of Cancer cells is multi-step process and dissemination is an initial step. Here we report a tamoxifen-controllable Twist1a-ERT2 transgenic zebrafish line as a new animal model for metastasis research, and demonstrate that this model can serve as a novel platform for discovery of antimetastasis drugs targeting metastatic dissemination of Cancer cells. By crossing Twist1a-ERT2 with xmrk (a homolog of hyperactive form of EGFR) transgenic zebrafish, which develops hepatocellular carcinoma, approximately 80% of the double transgenic zebrafish showed spontaneous cell dissemination of mCherry-labeled hepatocytes from the liver to the entire abdomen region and the tail region. The dissemination is accomplished in 5 days through induction of an epithelial-to-mesenchymal transition. Using this model, we conducted in vivo drug screening and identified three hit drugs. One of them, adrenosterone, an inhibitor for hydroxysteroid (11-beta) dehydrogenase 1 (HSD11β1), has a suppressor effect on cell dissemination in this model. Pharmacologic and genetic inhibition of HSD11β1 suppressed metastatic dissemination of highly metastatic human cell lines in a zebrafish xenotransplantation model. Through downregulation of Snail and Slug, adrenosterone-treated cells recovered expression of E-cadherin and Other epithelial markers and lost partial expression of mesenchymal markers compared with vehicle-treated cells. Taken together, our model offers a useful platform for the discovery of antimetastasis drugs targeting metastatic dissemination of Cancer cells. IMPLICATIONS: This study describes a transgenic zebrafish model for liver tumor metastasis and it has been successfully used for identification of some drugs to inhibit metastatic dissemination of human Cancer cells.

Products