Zebrafish Patient-Derived Xenograft Model as a Preclinical Platform for Uveal Melanoma Drug Discovery

Yin, Jie, Zhao, Gangyin, Kalirai, Helen ORCID: 0000-0002-4440-2576, Coupland, Sarah E ORCID: 0000-0002-1464-2069, Jochemsen, Aart G, Forn-Cuni, Gabriel, Wierenga, Annemijn PA, Jager, Martine J, Snaar-Jagalska, B Ewa and Groenewoud, Arwin (2023) Zebrafish Patient-Derived Xenograft Model as a Preclinical Platform for Uveal Melanoma Drug Discovery. PHARMACEUTICALS, 16 (4). 598-.

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Official URL: http://dx.doi.org/10.3390/ph16040598

Abstract

Uveal melanoma (UM) is a rare malignant cancer of the eye, with up to 50% of patients dying from metastasis, for which no effective treatment is available. Due to the rarity of the disease, there is a great need to harness the limited material available from primary tumors and metastases for advanced research and preclinical drug screening. We established a platform to isolate, preserve, and transiently recover viable tissues, followed by the generation of spheroid cultures derived from primary UM. All assessed tumor-derived samples formed spheroids in culture within 24 h and stained positive for melanocyte-specific markers, indicating the retention of their melanocytic origin. These short-lived spheroids were only maintained for the duration of the experiment (7 days) or re-established from frozen tumor tissue acquired from the same patient. Intravenous injection of fluorescently labeled UM cells derived from these spheroids into zebrafish yielded a reproducible metastatic phenotype and recapitulated molecular features of the disseminating UM. This approach allowed for the experimental replications required for reliable drug screening (at least 2 individual biological experiments, with <i>n</i> > 20). Drug treatments with navitoclax and everolimus validated the zebrafish patient-derived model as a versatile preclinical tool for screening anti-UM drugs and as a preclinical platform to predict personalized drug responses.

Item Type:	Article
Uncontrolled Keywords:	drug screening, drug toxicity, eye, oncology, uveal melanoma, xenograft, zebrafish
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	28 Sep 2023 10:19
Last Modified:	28 Sep 2023 10:20
DOI:	10.3390/ph16040598
Open Access URL:	https://doi.org/10.3390/ph16040598
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3173156