GDF15 Reprograms the Microenvironment to Drive Liver Metastasis of Uveal Melanoma.

Uveal melanoma is an aggressive tumor type that frequently results in fatal liver metastasis. A better understanding of the interactions between uveal melanoma and host cells in the tumor microenvironment that promote liver metastasis could lead to the development of therapeutic strategies. In this study, we used single-cell RNA-sequencing analysis of uveal melanoma-hepatic stellate cell (HSC) cocultures to explore the mechanisms by which uveal melanoma cells metastasize to the liver. HSCs enriched for uveal melanoma cell states that expressed genes implicated in cell survival, metabolic reprogramming, and growth differentiation factor 15 (GDF15)-mediated angiogenesis. The TGFβ family member GDF15 was associated with a metastatic uveal melanoma phenotype. Silencing of BAP1 in uveal melanoma 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 (ECM) proteins, inflammatory cytokines, and angiogenic factors, including IL8. Both exogenous GDF15 and IL8, as well as conditioned media from uveal melanoma-HSC cocultures, increased endothelial cell network formation in vitro, an effect that was blocked by anti-GDF15 antibodies. In multiple models of metastatic uveal melanoma, silencing of GDF15 inhibited the outgrowth of metastatic lesions, associated with reduced deposition of ECM and recruitment of endothelial cells. Together, these findings reveal that uveal melanoma liver metastasis development is dependent on GDF15-mediated remodeling of the liver microenvironment, which leads to an angiogenic response and matrix deposition that supports tumor growth. SIGNIFICANCE: GDF15 functions as a growth factor that helps drive the development of liver metastases in uveal melanoma by contributing to angiogenesis and matrix deposition, allowing for metastatic outgrowth.