Cancers

Simple Summary Uveal melanoma (UM) is the most common primary intraocular tumor in adults, with a high incidence of liver metastasis causing poor survival. However, the mechanisms underlying this liver tropism remain poorly understood. Our study focused on the roles of UM exosomes along the metastatic process. A comparison of protein cargos between exosomes derived from the primary UM tumor and metastasis reveals a prominent function of exosomes derived from parental cells, favoring the detachment of cells from the primary site. We also found that UM-derived exosomes played a significant role in the activation and transdifferentiation of human hepatic stellate cells (HHSCs), which contribute to the formation of a pre-metastatic niche in the liver, promote interaction with tumor cells, and ultimately might enhance the metastatic potential.Abstract UM is an aggressive intraocular tumor characterized by high plasticity and a propensity to metastasize in the liver. However, the underlying mechanisms governing liver tropism remain poorly understood. Given the emerging significance of exosomes, we sought to investigate the contribution of UM-derived exosomes to specific steps of the metastatic process. Firstly, we isolated exosomes from UM cells sharing a common genetic background and different metastatic properties. A comparison of protein cargo reveals an overrepresentation of proteins related to cytoskeleton remodeling and actin filament-based movement in exosomes derived from the parental cells that may favor the detachment of cells from the primary site. Secondly, we assessed the role of macrophages in reprogramming the HHSCs by exosomes. The activation of HHSCs triggered a pro-inflammatory and pro-fibrotic environment through cytokine production, upregulation of extracellular matrix molecules, and the activation of signaling pathways. Finally, we found that activated HHSCs promote increased adhesion and migration of UM cells. Our findings shed light on the pivotal role of exosomes in pre-metastatic niche construction in the liver.