Groenewoud, Arwin, Yin, Jie, Gelmi, Maria Chiara, Alsafadi, Samar, Nemati, Fariba, Decaudin, Didier, Roman-Roman, Sergio, Kalirai, Helen 
ORCID: 0000-0002-4440-2576, Coupland, Sarah E ORCID: 0000-0002-1464-2069, Jochemsen, Aart G et al (show 3 more authors)
(2023)
Patient-derived zebrafish xenografts of uveal melanoma reveal ferroptosis as a drug target.
CELL DEATH DISCOVERY, 9 (1).
183-.
Abstract
Uveal melanoma (UM) has a high risk to progress to metastatic disease with a median survival of 3.9 months after metastases detection, as metastatic UM responds poorly to conventional and targeted chemotherapy and is largely refractory to immunotherapy. Here, we present a patient-derived zebrafish UM xenograft model mimicking metastatic UM. Cells isolated from Xmm66 spheroids derived from metastatic UM patient material were injected into 2 days-old zebrafish larvae resulting in micro-metastases in the liver and caudal hematopoietic tissue. Metastasis formation could be reduced by navitoclax and more efficiently by the combinations navitoclax/everolimus and flavopiridol/quisinostat. We obtained spheroid cultures from 14 metastatic and 10 primary UM tissues, which were used for xenografts with a success rate of 100%. Importantly, the ferroptosis-related genes GPX4 and SLC7A11 are negatively correlated with the survival of UM patients (TCGA: n = 80; Leiden University Medical Centre cohort: n = 64), ferroptosis susceptibility is correlated with loss of BAP1, one of the key prognosticators for metastatic UM, and ferroptosis induction greatly reduced metastasis formation in the UM xenograft model. Collectively, we have established a patient-derived animal model for metastatic UM and identified ferroptosis induction as a possible therapeutic strategy for the treatment of UM patients.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Cancer, Prevention, Eye Disease and Disorders of Vision, Rare Diseases, Biotechnology, Cancer, 3 Good Health and Well Being |
| 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 10:05 |
| Last Modified: | 14 Mar 2024 18:45 |
| DOI: | 10.1038/s41420-023-01446-6 |
| Open Access URL: | https://doi.org/10.1038/s41420-023-01446-6 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3173149 |
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