Wietske van der Ent1, Claudia Burrello2, Amina F A S Teunisse3, Bruce R Ksander4, Pieter A van der Velden5, Martine J Jager5, Aart G Jochemsen3, B Ewa Snaar-Jagalska2. 1. Institute of Biology, Leiden University, Leiden, The Netherlands Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 2. Institute of Biology, Leiden University, Leiden, The Netherlands. 3. Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands. 4. Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, United States. 5. Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
Abstract
PURPOSE: 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. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
PURPOSE: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 humanuveal 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 humanuveal melanoma with demonstrated applicability for screening large libraries of compounds in drug discovery studies. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
Entities:
Keywords:
drug treatment; uveal melanoma; xenotransplantation; zebrafish
Authors: Wietske van der Ent; Claudia Burrello; Mark J de Lange; Pieter A van der Velden; Aart G Jochemsen; Martine J Jager; B Ewa Snaar-Jagalska Journal: Ocul Oncol Pathol Date: 2015-04-09
Authors: Chandrani Chattopadhyay; Dae Won Kim; Dan S Gombos; Junna Oba; Yong Qin; Michelle D Williams; Bita Esmaeli; Elizabeth A Grimm; Jennifer A Wargo; Scott E Woodman; Sapna P Patel Journal: Cancer Date: 2016-03-15 Impact factor: 6.860