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VEGF-induced Nrdp1 deficiency in vascular endothelial cells promotes cancer metastasis by degrading vascular basement membrane

Oncogene volume 43, pages 1836–1851 (2024)Cite this article

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Abstract

Vascular endothelial cells (VECs) are key players in the formation of neovessels and tumor metastasis, the ultimate cause of the majority of cancer-related human death. However, the crosstalk between VECs and metastasis remain greatly elusive. Based on our finding that tumor-associated VECs present significant decrease of Nrdp1 protein which is closely correlated with higher metastatic probability, herein we show that the conditional medium from hypoxia-incubated cancer cells induces extensive Nrdp1 downregulation in human and mouse VECs by vascular endothelial growth factor (VEGF), which activates CHIP, followed by Nrdp1 degradation in ubiquitin-proteasome-dependent way. More importantly, lung metastases of cancer cells significantly increase in conditional VECs Nrdp1 knockout mice. Mechanically, Nrdp1 promotes degradation of Fam20C, a secretory kinase involved in phosphorylating numerous secreted proteins. Reciprocally, deficiency of Nrdp1 in VECs (ecNrdp1) results in increased secretion of Fam20C, which induces degradation of extracellular matrix and disrupts integrity of vascular basement membrane, thus driving tumor metastatic dissemination. In addition, specific overexpression of ecNrdp1 by Nrdp1-carrying adeno-associated virus or chemical Nrdp1 activator ABPN efficiently mitigates tumor metastasis in mice. Collectively, we explore a new mechanism for VEGF to enhance metastasis and role of Nrdp1 in maintaining the integrity of vascular endothelium, suggesting that ecNrdp1-mediated signaling pathways might become potential target for anti-metastatic therapies.

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Fig. 1: VECs in tumors present lower expression of Nrdp1 protein.
Fig. 2: Cancer cells secreted VEGF induces Nrdp1 degradation in VECs.
Fig. 3: Deficiency of ecNrdp1 facilitates cancer cell metastasis in vivo.
Fig. 4: EcNrdp1 deficiency has no effect on VECs-tumor cell adhesion and VEC gap junctions.
Fig. 5: EcNrdp1 deletion disrupts the integrity of vascular basement membrane.
Fig. 6: Deletion of ecNrdp1 facilitates metastasis by Fam20C expression.
Fig. 7: Increased ecNrdp1 by gene delivery or chemical induction alleviates lung metastatic burden in mice.

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All data generated or analyzed during this study are included in this published article and its supplementary information files, or available from the corresponding author on reasonable request.

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Acknowledgements

This work is supported by National Key R&D Program of China (2020YFA0803403), National Natural Science Foundation (82293661, 82070893, 92253303, 82200185), Shanghai Scientific and Technological Innovation Action Plan (20JC1410100), Innovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20211800). We thank Yao-Yao Τu for kindly providing human umbilical cord (International Peace Maternity and Child Health Hospital, SJTUSM), Prof. Dr. Sorakin for kindly providing laminin α5 antibody (Institute of Physiological Chemistry and Pathobiochemistry University of Muenster) and Prof. Lei Wang for kindly providing Fam20C antibody (Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences).

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  1. These authors contributed equally: Qing-Qing Li, Meng Guo.

Authors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China

    Qing-Qing Li, Meng Guo, Guang-Huan He, Kai-Hua Xi, Mei-Yi Zhou & Guo-Qiang Chen

  2. Hainan Academy of Medical Sciences and School of Basic Medicine, Hainan Medical University, Hainan, 570000, China

    Rong-Yi Shi & Guo-Qiang Chen

  3. Key Laboratory of Pediatric Hematology and Oncology in National Health Commission, Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, SJTU-SM, Shanghai, 200127, China

    Rong-Yi Shi

  4. Institute of Aging & Tissue Regeneration, State Key Laboratory of Systems Medicine for Cancer, Research Units of Stress and Tumor (2019RU043), Chinese Academy of Medical Sciences, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China

    Guo-Qiang Chen

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Contributions

QL, MG, and GC conceived and designed the project. QL and MG performed most of the experiments. GH, KX, and MZ helped with biochemistry experiments and animal experiments. RS performed the immune experiments. GC, MG, and RS wrote the manuscript and all authors contributed to the writing and/or critical review of the manuscript.

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Correspondence to Meng Guo, Rong-Yi Shi or Guo-Qiang Chen.

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Li, QQ., Guo, M., He, GH. et al. VEGF-induced Nrdp1 deficiency in vascular endothelial cells promotes cancer metastasis by degrading vascular basement membrane. Oncogene 43, 1836–1851 (2024). https://doi.org/10.1038/s41388-024-03038-9

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