title: Modeling of human uveal melanoma in zebrafish xenograft embryos.
abstract: OBJECTIVE
  Uveal melanoma (UM) is fatal in up to 50% of patients because of liver metastases that are refractory to therapies currently available. While murine xenograft models for human uveal melanoma are available, they have limited utility for screening large compound libraries in drug discovery studies. Therefore, new robust preclinical models are needed that can efficiently evaluate drug efficacy for treatment of this malignancy.
  
  
  METHODS
  Uveal melanoma cell lines generated from primary tumors (92.1, Mel270) and metastases (OMM2.3, OMM2.5, OMM1) were injected into the yolk of 2-day-old zebrafish embryos. After 6 days, proliferation and active migration was quantified via automated confocal image analysis. To determine the suitability of this xenotransplantation model for drug testing, drugs with three different activities (dasatinib, quisinostat, and MLN-4924) were added to the water of uveal melanoma-engrafted embryos.
  
  
  RESULTS
  All tested UM cell lines proliferated and migrated in the embryos; significant differences could be discerned between cell lines: Cells derived from metastases showed more migration and proliferation than cells derived from the primary tumors, and provided preclinical models for drug testing. Addition of the Src-inhibitor dasatinib in the water of engrafted embryos reduced proliferation and migration of high Src-expressing 92.1 cells, but did not affect low Src-expressing metastatic OMM2.3 cells. Two experimental anticancer drugs, quisinostat (a histone deacetylase inhibitor) and MLN-4924 (neddylation pathway inhibitor), blocked migration and proliferation of 92.1 and OMM2.3.
  
  
  CONCLUSIONS
  We established a zebrafish xenograft model of human uveal melanoma with demonstrated applicability for screening large libraries of compounds in drug discovery studies.
authors.affiliation: Institute of Biology, Leiden University, Leiden, The Netherlands Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Wietske
authors.initials: W
authors.lastname: van der Ent
authors.affiliation: Institute of Biology, Leiden University, Leiden, The Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Burrello
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Amina F A S
authors.initials: AF
authors.lastname: Teunisse
authors.affiliation: Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Ksander
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van der Velden
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Aart G
authors.initials: AG
authors.lastname: Jochemsen
authors.affiliation: Institute of Biology, Leiden University, Leiden, The Netherlands.
authors.forename: B Ewa
authors.initials: BE
authors.lastname: Snaar-Jagalska
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000196:embryology*; D009374:Neoplasms, Experimental / Q000196:embryology*; D014407:Tumor Cells, Cultured; D014604:Uveal Neoplasms / Q000188:drug therapy / Q000196:embryology*; D015027:Zebrafish / Q000196:embryology; D000098943:Uveal Melanoma
chemical_list: D000970:Antineoplastic Agents
keywords: drug treatment; uveal melanoma; xenotransplantation; zebrafish