Abstract

Approximately 50% of uveal melanoma (UM) patients develop treatment-resistant liver metastases, surviving less than one year after diagnosis. While BRCA1-associated protein 1 ( BAP1 ) deficiency strongly correlates with UM metastasis, its mechanistic role remains unclear. Through integrated analysis of four UM cohorts and functional experiments validation, we identified S100 calcium binding protein A6 (S100A6) as a key metastasis-associated gene consistently upregulated in BAP1 -deficient UM. Mechanistically, BAP1 deficiency enhances H2AK119ub deposition and Pol II recruitment at the S100A6 promoter, activating its transcription. Notably, we discovered that S100A6 functions as a novel ligand of fibroblast growth factor receptor 3 (FGFR3), triggering sustained signaling distinct from canonical ligands and activating inflammatory cancer-associated fibroblasts. Genetic or pharmacological targeting of S100A6-FGFR3 signaling effectively suppressed BAP1 -deficient UM metastasis in preclinical models, highlighting the therapeutic potential of targeting this signaling pathway. Overall, our findings establish S100A6 as a critical mediator of hepatic metastasis in BAP1 -deficient UM through FGFR3-dependent tumor microenvironment activation, revealing its therapeutic potential.