A Multi-Faceted Approach to Uncover Novel Vulnerabilities in Uveal Melanoma: From Etiology to the Identification of Prognostic Biomarkers.

Background. Uveal Melanoma (UM) is the most common primary intraocular malignancy in adults. Its clinical management, in the metastatic state, remains a significant challenge, characterized by inherent aggressiveness and limited systemic therapeutic options. Despite substantial progress in genomic prognostic stratification, the unpredictable nature of the disease in some patients and the lack of effective treatments underscore the urgent need for a deeper understanding of both etiological factors and molecular mechanisms driving progression. Aims. This study adopted a multi-faceted approach focused on three main objectives: i) To elucidate the potential etiological role of Blue Light (BL) exposure; ii) To develop genetically defined cellular models to reproduce the key molecular alterations of aggressive UM (GNA11 and BAP1 mutations); and iii) To identify and validate novel prognostic biomarkers within the Chromosome 8q gain region. Results. BL exposure in melanocyte models generated mutational signatures (SBS1 and SBS5) aligned with those typical of UM, providing direct evidence that BL may act as an "additional hit" in tumorigenesis, distinct from UV-induced damage. Unexpectedly, a BL complex oxidative stress response was observed, characterized by an overall increase in ROS but a reduction in H2O2 production. In parallel, the first GNA11Q209L cellular models were successfully generated to reproduce the key alterations driving aggressive UM for in vitro and in vivo functional studies. Furthermore, bioinformatic, immunohistochemical and NGS analysis of two UM’s patients cohorts for the Chr 8q status identified NDUFB9 and LAPTM4B as potential functional drivers, whose expression enabled the development of a robust Multigene Score (MGS) highly potent in stratifying patients at high risk of disease-specific mortality. Conclusion and Discussion. This work provides novel etiological insights into the potential role of BL and introduces a reliable prognostic tool (MGS) superior to single markers. The identification of NDUFB9 (involved in mitochondrial metabolism) and LAPTM4B (implicated in autophagy and drug resistance) as probable functional drivers of the metastatic phenotype suggests these genes are not merely passenger, but represent promising therapeutic targets, particularly within the context of UM's intrinsic resistance. Further functional validation of these genes is crucial. Future studies will focus on completing the creation of more complex in vivo mouse models (GNA11+BAP1) for metastatic evaluation. Furthermore, the application of spatial transcriptomics (Xenium) on metastatic samples treated with Tebentafusp will be essential to map therapeutic cellular interactions within the tumor microenvironment and spatially validate the 8q drivers at high resolution, guiding the next generation of treatment strategies.