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ITGB2-ICAM1 axis promotes liver metastasis in BAP1-mutated uveal melanoma with retained hypoxia and ECM signatures

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Abstract

Purpose

Uveal melanoma (UM) with BAP1 inactivating mutations has a high risk of metastasis, but the mechanism behind BAP1 deficiency driving UM metastasis is unknown.

Methods

We analyzed the single-cell RNA sequencing (scRNA-Seq) data comprised primary and metastatic UM with or without BAP1 mutations (MUTs) to reveal inter- and intra-tumor heterogeneity among different groups. Then, an immune-competent mouse liver metastatic model was used to explore the role of ITGB2-ICAM1 in BAP1-associated UM metastasis.

Results

Cluster 1 tumor cells expressed high levels of genes linked to tumor metastasis, such as GDF15, ATF3, and CDKN1A, all of which are associated with poor prognosis. The strength of communication between terminally exhausted CD8+ T cells and GDF15hiATF3hiCDKN1Ahi tumor cells was enhanced in BAP1-mutated UM, with CellChat analysis predicting strong ITGB2-ICAM1 signaling between them. High expression of either ITGB2 or ICAM1 was a worse prognostic indicator. Using an immune-competent mouse liver metastatic model, we indicated that inhibiting either ICAM1 or ITGB2 prevented liver metastasis in the BAP1-mutated group in vivo. The inhibitors primarily inhibited hypoxia- and ECM-related pathways indicated by changes in the expression of genes such as ADAM8, CAV2, ENO1, PGK1, LOXL2, ITGA5, and VCAN. etc.

Conclusion

This study suggested that the ITGB2-ICAM1 axis may play a crucial role for BAP1-associated UM metastasis by preserving hypoxia- and ECM- related signatures, which provide a potential strategy for preventing UM metastasis in patients with BAP1 mutation.

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Data Availability

Sequence data that support the findings of this study have been deposited in NCBI database with the primary accession code PRJNA975671.

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Acknowledgements

We are grateful to Prof. Hong Tu and Dr. Qian Li for their assistance in generating the liver metastatic mouse model. The work was supported by grants from National Natural Science Foundation of China (32170924), Science and Technology Commission of Shanghai Municipality (21140901600, 23ZR1438400), Shanghai Jiaotong University School of Medicine (02.101005.001.29.38 A), State Key Laboratory of Oncogenes and Related Genes (SB21-22, ZZ-21-13rcpy, ZZ-GCYJ-23-02, ZZ-94-2313), China Postdoctoral Science Foundation (2022M722115).

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Author notes

  1. Ai Zhuang and Dongxi Xiang contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai, China

    Jiaoduan Li, Dongyan Cao & Dongxi Xiang

  2. Department of Biliary-Pancreatic Surgery, the Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Jiaoduan Li, Dongyan Cao & Dongxi Xiang

  3. Department of Ultrasound, the Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China

    Lixin Jiang & Yiwen Zheng

  4. Shanghai OneTar Biomedicine, Shanghai, China

    Siyuan Shao

  5. Department of Ophthalmology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

    Ai Zhuang

  6. Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China

    Ai Zhuang

  7. Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, China

    Dongxi Xiang

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Contributions

J.L., S.S., Y.Z., A.Z. and D.X. designed and performed experiments; J.L., D.C., L.J., and Y.Z. analyzed the data; J.L. and D.X. wrote and edited the manuscript; D.X. supervised the study, obtained funding, and provided critical review. All authors approved the final version of the manuscript.

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Correspondence to Ai Zhuang or Dongxi Xiang.

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Ethics approval

Animal experiments were performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals and relevant Chinese laws and regulations. The protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of Shanghai Jiao Tong University, the Animal Protocol number is RJ2022-1010. Ethical approval was obtained from the Research Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University.

Competing interests

The authors Dongxi Xiang, Jiaoduan Li, Lixin Jiang have submitted a patent (Application NO: 202310685260.6) related to this work. Dongxi Xiang is an editorial board member. Siyuan Shao is an employee of Shanghai OneTar Biomedicine.

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Li, J., Cao, D., Jiang, L. et al. ITGB2-ICAM1 axis promotes liver metastasis in BAP1-mutated uveal melanoma with retained hypoxia and ECM signatures. Cell Oncol. (2023). https://doi.org/10.1007/s13402-023-00908-4

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