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S100A6 promotes liver metastasis by activating FGFR3 signaling in BAP1-deficient uveal melanoma

Oncogene (2026)Cite this article

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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.

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Fig. 1: S100A6 overexpression correlates with metastatic progression and predicts poor prognosis in BAP1-deficient uveal melanoma.
Fig. 2: S100A6 drives metastatic progression in BAP1-deficient uveal melanoma.
Fig. 3: BAP1 loss drives S100A6 transcriptional activation through H2AK119ub deposition and enhanced RNA polymerase II recruitment.
Fig. 4: S100A6 activates hepatic metastasis niche through FGFR3-mediated CAFs reprogramming.
Fig. 5: Therapeutic targeting of FGFR3 abrogates S100A6-mediated pro-metastatic niche formation.
Fig. 6: FGFR3 inhibition suppresses metastatic progression in BAP1-deficient uveal melanoma.

Data availability

The data and all plasmids that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

The code used for the bioinformatics analysis in this study is available at https://github.com/ZCR-study/BAP1_S100A6_FGFR3---Uveal-Melanoma.

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Acknowledgements

Serums from patients with UM were kindly provided by Ke Wang from National Health Commission Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, China.

Funding

This work was supported by the National Natural Science Foundation of China (82304517 to Tao Yuan) and the Key project of Hangzhou Agricultural and Social Development Program (20241203A19 to Bo Yang).

Author information

Authors and Affiliations

  1. College of Pharmaceutical Science, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Zhejiang University, Hangzhou, China

    Yonghao Li, Churun Zheng, Yanting Liang, Yue Liu, Renhua Gai, Tao Yuan, Qiaojun He, Bo Yang & Hong Zhu

  2. Sydney Pharmacy School, The University of Sydney, Camperdown, NSW, Australia

    Fanfan Zhou

  3. National Health Commission Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, China

    Xue Zhu, Jing Fang & Ke Wang

  4. Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, China

    Xue Zhu, Jing Fang & Ke Wang

  5. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Yanyan Zhuang & Ke Wang

  6. School of Medicine, Hangzhou City University, Hangzhou, China

    Bo Yang

  7. Department of Hepatobiliary Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, China

    Xin Dong

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  1. Yonghao Li
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Contributions

Yonghao Li: Conceptualization, data curation, formal analysis, validation, investigation, visualization, methodology, writing–original draft. Churun Zheng: Conceptualization, data curation, software, visualization. Yanting Liang: Validation, investigation, visualization. Yue Liu: Validation, investigation, visualization. Fanfan Zhou: Validation, investigation, methodology. Xue Zhu: Validation, investigation, methodology. Jing Fang: Validation, investigation, methodology. Renhua Gai: Resources, supervision, methodology. Yanyan Zhuang: Resources, supervision, methodology. Ke Wang (Sun Yat-Sen University): Resources, supervision, methodology. Tao Yuan: Resources, supervision, methodology, funding acquisition. Qiaojun He: Resources, supervision, methodology. Bo Yang: Conceptualization, resources, supervision, funding acquisition, project administration, writing–review and editing. Ke Wang (Jiangsu Institute of Nuclear Medicine): Validation, investigation, methodology, supervision. Xin Dong: Resources, supervision, methodology, supervision. Hong Zhu: Conceptualization, resources, supervision, funding acquisition, project administration, writing–review and editing.

Corresponding authors

Correspondence to Ke Wang, Xin Dong or Hong Zhu.

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Li, Y., Zheng, C., Liang, Y. et al. S100A6 promotes liver metastasis by activating FGFR3 signaling in BAP1-deficient uveal melanoma. Oncogene (2026). https://doi.org/10.1038/s41388-026-03766-0

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