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

Language
en
Document Type
Article
Issue Date
2023-05-11
First published
2023-04-15
Issue Year
2023
Authors
Yin, Jie
Zhao, Gangyin
Kalirai, Helen
Coupland, Sarah E.
Jochemsen, Aart G.
Forn-Cuní, Gabriel
Wierenga, Annemijn P. A.
Jager, Martine J.
Snaar-Jagalska, B. Ewa
Groenewoud, Arwin
Editor
Publisher
MDPI
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 n > 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.

Journal Title
Pharmaceuticals
Volume
16
Issue
4
Citation
Pharmaceuticals 16.4 (2023): 598. <https://www.mdpi.com/1424-8247/16/4/598>
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