Ramos Raquel, Vinyals Antònia, Campos-Martin Rafael, Cabré Eduard, Bech Joan Josep, Vaquero Javier, Gonzalez-Sanchez Ester, Bertran Esther, Ferreres Josep Ramon, Lorenzo Daniel, De La Torre Carolina G, Fabregat Isabel, Caminal Jose Maria, Fabra Àngels
TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), ISCIII, 28029 Madrid, Spain.
Cancers (Basel). 2024 Aug 27;16(17):2977. doi: 10.3390/cancers16172977.
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.
葡萄膜黑色素瘤（UM）是一种侵袭性眼内肿瘤，具有高可塑性且倾向于转移至肝脏。然而，关于其肝脏嗜性的潜在机制仍知之甚少。鉴于外泌体的重要性日益凸显，我们试图研究UM来源的外泌体在转移过程特定步骤中的作用。首先，我们从具有共同遗传背景和不同转移特性的UM细胞中分离出外泌体。蛋白质组分析显示，来自亲代细胞的外泌体中与细胞骨架重塑和基于肌动蛋白丝运动相关的蛋白质含量过高，这可能有利于细胞从原发部位脱离。其次，我们评估了巨噬细胞在外泌体重编程肝星状细胞（HHSCs）中的作用。HHSCs的激活通过细胞因子产生、细胞外基质分子上调以及信号通路激活引发了促炎和促纤维化环境。最后，我们发现活化的HHSCs促进了UM细胞的粘附和迁移增加。我们的研究结果揭示了外泌体在肝脏转移前微环境构建中的关键作用。
