Clonal determinants of organotropism and survival in metastatic uveal melanoma

Abstract

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.