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Anti-angiogenesis and anti-immunosuppression gene therapy through targeting COUP-TFII in an in situ glioblastoma mouse model

Cancer Gene Therapy volume 31, pages 1135–1150 (2024)Cite this article

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Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain cancer; angiogenesis and immunosuppression exacerbate GBM progression. COUP-TFII demonstrates pro-angiogenesis activity; however, its role in glioma progression remains unclear. This study revealed that COUP-TFII promotes angiogenesis in gliomas by inducing transdifferentiation of glioma cells into endothelial-like cells. Mechanistic investigation suggested that COUP-TFII as a transcription factor exerts its function via binding to the promoter of TXNIP. Interestingly, COUP-TFII knockdown attenuated tumorigenesis and tumor progression in an immunocompetent mouse model but promoted tumor progression in an immuno-deficient mouse model. As an explanation, repression of COUP-TFII induces cellular senescence and activates immune surveillance in glioma cells in vitro and in vivo. In addition, we used heparin–polyethyleneimine (HPEI) nanoparticles to deliver COUP-TFII shRNA, which regulated tumor angiogenesis and immunosuppression in an in situ GBM mouse model. This study provides a novel strategy and potential therapeutic targets to treat GBM.

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Fig. 1: COUP-TFII is overexpressed in tumor tissues and inversely related to clinical prognosis of GBM patients.
Fig. 2: Knockdown of COUP-TFII inhibits the proliferation and invasion of glioma cells.
Fig. 3: COUP-TFII promotes glioma cells to transform into endothelium-like cells in vitro.
Fig. 4: Knocking down COUP-TFII by virus unimaginably promotes tumor progression in immuno-deficient mouse model while attenuates tumor progression in immunologically mouse model.
Fig. 5: COUP-TFII suppression enhances the antigen presentation of glioma cells in vitro.
Fig. 6: Fabrication and characterization of HPEI nanoparticles.
Fig. 7: Delivery of COUP-TFII shRNA by HPEI nanoparticles for in situ GBM treatment.

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Data availability

All datasets generated and analyzed during this study are included in this published article and its Supplementary Information files. Additional data are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (31900441, 82373097, 82172565, and 32100006; to Jing Du, Jiong Deng, and WD), China Postdoctoral Science Foundation (2023M742089; to FW), Natural Science Foundation of Shandong Province (ZR2019MC026, ZR2023QH080, ZR2022QH192, and ZR2023MH033; to Jing Du, FW, WC, and WF), Funds of Shandong Traditional Chinese Medicine Science and Technology Development Project (2019-0514; to Jing Du), Qilu Outstanding Young Talents in Health Project (to Jing Du), Double-Hundred Project and Taishan Scholarship (WSR2023085; to CAS and Jing Du), Ministry of Education “Chunhui” Plan International Cooperation Project (HZKY20220459; to Jing Du), Research Foundation of Binzhou Medical University Hospital (2022-01; to FW). We would like to thank Editage (www.editage.cn) for English language editing.

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Author notes

  1. These authors contributed equally: Fei Wang, Shuo Zhang, Fengjiao Sun, Weiwei Chen.

Authors and Affiliations

  1. Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China

    Fei Wang, Shuo Zhang, Fengjiao Sun, Weiwei Chen, Cuilan Liu, Hongliang Dong, Bingjie Cui, Lingyu Li, Bin Liu, Wanfeng Fan, Jiong Deng & Jing Du

  2. Medical Integration and Practice Center, Qilu Hospital of Shandong University, Shandong University, 250100, Jinan, PR China

    Fei Wang & Xiuwen Wang

  3. Department of Gynecology, Binzhou Medical University Hospital, 256600, Binzhou, PR China

    Shuo Zhang & Jing Du

  4. College of Biological and Environmental Engineering, Shandong University of Aeronautics, 256600, Binzhou, PR China

    Chunlong Sun & Wen Du

  5. Johannes Kepler University, Altenbergerstraße 69, 4040, Linz, Austria

    Clemens A. Schmitt

  6. Department of Hematology and Oncology, Kepler University Hospital, Krankenhausstraße 9, 4020, Linz, Austria

    Clemens A. Schmitt

  7. Medical Department of Hematology, Oncology and Tumor Immunology, and Molekulares Krebsforschungszentrum – MKFZ, Campus Virchow Klinikum, Charité-Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353, Berlin, Germany

    Clemens A. Schmitt

  8. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, 13125, Berlin, Germany

    Clemens A. Schmitt

  9. Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site, Berlin, Germany

    Clemens A. Schmitt

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  1. Fei Wang
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  2. Shuo Zhang
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Contributions

Jing Du and Jiong Deng conceived the original concept and initiated this project. Jing Du and XW designed the experiment and supervised the entire project. FW, FS, BC, BL, and CL established the tumor-bearing mouse models. FW, SZ, and LL carried out in vitro cell experiments. FW, SZ, WD, and CS performed histologic analysis under the supervision of Jing Du. HD and WC did the CHIP-seq. WF, SZ, and WC helped in data collection. Jing Du, CAS, and XW provided critical feedback and helped in review of the article. FW and Jing Du wrote the paper with input from other authors.

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Correspondence to Xiuwen Wang or Jing Du.

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Wang, F., Zhang, S., Sun, F. et al. Anti-angiogenesis and anti-immunosuppression gene therapy through targeting COUP-TFII in an in situ glioblastoma mouse model. Cancer Gene Ther 31, 1135–1150 (2024). https://doi.org/10.1038/s41417-024-00799-z

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