GDF15 Reprograms the Microenvironment to Drive Liver Metastasis of Uveal Melanoma

Uveal melanoma (UM) is an aggressive tumor type that frequently results in fatal liver metastasis. A better understanding of the interactions between UM and host cells in the tumor microenvironment that promote liver metastasis could lead to the development of therapeutic strategies. Here, we used single-cell RNA-sequencing (scRNA-seq) analysis of UM-hepatic stellate cell (HSC) co-cultures to explore the mechanisms by which UM cells metastasize to the liver. HSCs enriched for UM cell states that expressed genes implicated in cell survival, metabolic reprogramming, and growth differentiation factor (GDF)-15-mediated angiogenesis. The TGF-β family member GDF15 was associated with a metastatic UM phenotype. Silencing of BAP1 in UM cells led to increased GDF15 expression and accumulation of H3K27ac marks at the GDF15 promoter. Treatment of HSCs with GDF15 led to increased expression of extracellular matrix proteins, inflammatory cytokines, and angiogenic factors, including IL-8. Both exogenous GDF15 and IL-8, as well as conditioned media from UM-HSC co-cultures, increased endothelial cell network formation in vitro, an effect that was blocked by anti-GDF15 antibodies. In multiple models of metastatic UM, silencing of GDF15 inhibited the outgrowth of metastatic lesions, associated with reduced deposition of extracellular matrix and recruitment of endothelial cells. Together, these findings reveal that UM liver metastasis development is dependent upon GDF15-mediated remodeling of the liver microenvironment, which leads to an angiogenic response and matrix deposition that supports tumor growth.