biostudies-literatureUnknownSriramareddy SNNEI NIH HHSNCI NIH HHSUveal melanoma (UM) results in fatal liver metastasis, yet little is known about the interactions between UM and host cells in the tumor microenvironment that promote this distinctive proclivity. Here, we used single cell (sc)-RNA-Seq analysis of UM-hepatic stellate cell (HSC) co-cultures to demonstrate that HSCs enriched for UM cell states that expressed genes implicated in cell survival, metabolic reprogramming and angiogenesis. A lead candidate driver of HSC reprogramming was the TGF-β family member GDF15, which 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 extracellular matrix proteins, inflammatory cytokines bioRxiv : the preprint server for biology2025.05.07.652654https://www.ebi.ac.uk/biostudies/studies/S-EPMC12247901biostudies-literatureGDF15 reprograms the microenvironment to drive the development of uveal melanoma liver metastases.PMC12247901P30 CA247796R01 CA256193P30 CA142543P30 CA076292P30 EY030413Kurtenbach SChen YADollar JJSiddarajappa NNguyen THarbour JWSmalley KSMLicht JDPark JSKuznetsoff JNAdams DJSriramareddy SNCorrea ZMfalseGDF15 reprograms the microenvironment to drive the development of uveal melanoma liver metastases.Uveal melanoma (UM) results in fatal liver metastasis, yet little is known about the interactions between UM and host cells in the tumor microenvironment that promote this distinctive proclivity. Here, we used single cell (sc)-RNA-Seq analysis of UM-hepatic stellate cell (HSC) co-cultures to demonstrate that HSCs enriched for UM cell states that expressed genes implicated in cell survival, metabolic reprogramming and angiogenesis. A lead candidate driver of HSC reprogramming was the TGF-β family member GDF15, which 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 extracellular matrix proteins, inflammatory cytokines 2025-01-01T00:00:00Z2025 May2025-08-23T03:08:54.994Z2025-08-23T03:08:54.994ZS-EPMC122479014065465110.1101/2025.05.07.652654