Molecular characterization of metastatic progression in patient derived xenograft models of malignant uveal melanoma

Abstract

Aims/Purpose: It has been observed that large UM lesions with significant infiltration of macrophages and CD8+ T cells exhibit specific genetic profiles that increase the risk of liver metastasis. Additionally, recent discoveries of DNA methylation changes in Class 2 tumours undergoing metastasis suggest a potential role of epigenetic alterations in UM progression.Methods: To identify factors involved in UM metastasis, we implanted 25 viable UM tumours (consisting of 11 Class 1 tumours with a good prognosis and 14 Class 2 tumours with a poor prognosis) subcutaneously into immunodeficient NSG mice. From these, we successfully established ten patient‐derived xenografts (PDXs) using Class 2 tumour tissues. Two metastatic PDXs were derived from liver (UM50) and peritoneal (UM58) metastases spontaneously developed on mice.Results: Comprehensive characterization of both primary tumours and PDX tissues was performed using bulk transcriptomics and methylomics techniques. Among the enriched metabolic pathways identified in the liver metastasis‐derived PDX tissue of sample UM50 compared to the PDX tissue from the primary tumour, four were related to epigenetic regulation, including the activation of rRNA expression by ERCC6 and EHMT2, methylation of histones and DNA by Polycomb Repressive Complex 2 (PRC2), regulation of rRNA expression by NAD‐dependent Deacetylase Sirtuin‐1, and the DNA methylation pathway.Conclusions: These findings highlight the potential importance of epigenetic deregulation in UM progression and provide a foundation for future investigations. Further analysis using the Chromium Single Cell ATAC platform to examine chromatin accessibility at the single‐cell level in primary and metastatic PDX tissues of UM50 and UM58 that are ongoing can contribute to unravelling the precise role of epigenetic alterations in UM metastasis. Continued research in this area may lead to the development of novel therapeutic strategies targeting epigenetic mechanisms and improving outcomes for patients with metastatic UM.