Clonal determinants of organotropism and survival in metastatic uveal melanoma

Uveal melanoma (UM), the most common intraocular primary cancer in adults, demonstrates a unique proclivity for liver metastasis. To understand the molecular underpinnings of this organotropism, we analyzed the genomic features of liver and extrahepatic UM metastases, identifying distinct molecular signatures that mirror the clonal diversity in primary UM tumors. Liver metastases were enriched in BAP1 mutations and exhibited a higher prevalence of monosomy 3 compared to extrahepatic metastases. Analysis of the tumor-liver microenvironment crosstalk at the single-cell level underscored a significant role for hepatic stellate cells in facilitating UM growth and establishment in the liver. Notably, within the primary tumor, clones that demonstrated a high affinity for the liver, compared to those with low liver affinity, exhibited a distinct transcriptional profile characterized by the upregulation of pathways that activate hepatic stellate cells, specifically involving TGF-β signaling, cytokine signaling, extracellular matrix remodeling, and angiogenesis. Liver-tropic clones displayed not only an increased affinity for liver colonization but were also associated with worse survival outcomes, underscoring the adverse prognostic significance of hepatic metastases in UM. Our findings demonstrate that trajectories of metastatic dissemination and patient survival in UM are established early in the primary tumor’s evolution, opening pathways for the development of targeted therapeutic interventions to improve patient outcomes.

葡萄膜黑色素瘤（UM）是成人最常见的眼内原发性癌症，具有独特的肝转移倾向。为了解这种器官趋向性的分子基础，我们分析了肝转移和肝外UM转移的基因组特征，确定了不同的分子特征，这些特征反映了原发性UM肿瘤中的克隆多样性。肝转移中BAP1突变富集，与肝外转移相比，3号染色体单体缺失的发生率更高。在单细胞水平对肿瘤 - 肝脏微环境相互作用的分析强调了肝星状细胞在促进UM在肝脏中生长和定植方面的重要作用。值得注意的是，在原发性肿瘤中，与对肝脏亲和力低的克隆相比，对肝脏具有高亲和力的克隆表现出独特的转录谱，其特征是激活肝星状细胞的通路（特别是涉及转化生长因子 - β信号传导、细胞因子信号传导、细胞外基质重塑和血管生成）上调。亲肝性克隆不仅对肝脏定植的亲和力增加，而且与更差的生存结果相关，这突出了UM肝转移的不良预后意义。我们的研究结果表明，UM的转移扩散轨迹和患者生存情况在原发性肿瘤演变的早期就已确定，这为开发靶向治疗干预措施以改善患者预后开辟了途径。