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ResearchIn-Press PreviewCell biologyVascular biology Open Access | 10.1172/JCI201769

Endothelial deletion of the neddylation E2 enzyme UBE2M inhibits tumor growth by promoting non-productive angiogenesis

Xinyi Jiang,1 Jie Zhang,2 Li Zhou,1 Zonglin Li,3 Ningcong Sun,1 Xian Xu,4 Jisong Zhang,4 Yizhou Huang,5 Xue Zhang,1 Enguo Chen,4 Hongqiang Cheng,3 and Yuehai Ke1

1Department of Pathology and Pathophysiology and Department of Respiratory M, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

3Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

4Department of Respiratory and Critical Care Medicine, Regional medical center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine,, Hangzhou, China

Find articles by Jiang, X. in: PubMed | Google Scholar

1Department of Pathology and Pathophysiology and Department of Respiratory M, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

3Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

4Department of Respiratory and Critical Care Medicine, Regional medical center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine,, Hangzhou, China

Find articles by Zhang, J. in: PubMed | Google Scholar

1Department of Pathology and Pathophysiology and Department of Respiratory M, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

3Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

4Department of Respiratory and Critical Care Medicine, Regional medical center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine,, Hangzhou, China

Find articles by Zhou, L. in: PubMed | Google Scholar

1Department of Pathology and Pathophysiology and Department of Respiratory M, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

3Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

4Department of Respiratory and Critical Care Medicine, Regional medical center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine,, Hangzhou, China

Find articles by Li, Z. in: PubMed | Google Scholar

1Department of Pathology and Pathophysiology and Department of Respiratory M, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

3Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

4Department of Respiratory and Critical Care Medicine, Regional medical center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine,, Hangzhou, China

Find articles by Sun, N. in: PubMed | Google Scholar

1Department of Pathology and Pathophysiology and Department of Respiratory M, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

3Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

4Department of Respiratory and Critical Care Medicine, Regional medical center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine,, Hangzhou, China

Find articles by Xu, X. in: PubMed | Google Scholar

1Department of Pathology and Pathophysiology and Department of Respiratory M, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

3Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

4Department of Respiratory and Critical Care Medicine, Regional medical center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine,, Hangzhou, China

Find articles by Zhang, J. in: PubMed | Google Scholar

1Department of Pathology and Pathophysiology and Department of Respiratory M, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

3Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

4Department of Respiratory and Critical Care Medicine, Regional medical center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine,, Hangzhou, China

Find articles by Huang, Y. in: PubMed | Google Scholar

1Department of Pathology and Pathophysiology and Department of Respiratory M, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

3Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

4Department of Respiratory and Critical Care Medicine, Regional medical center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine,, Hangzhou, China

Find articles by Zhang, X. in: PubMed | Google Scholar

1Department of Pathology and Pathophysiology and Department of Respiratory M, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

3Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

4Department of Respiratory and Critical Care Medicine, Regional medical center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine,, Hangzhou, China

Find articles by Chen, E. in: PubMed | Google Scholar

1Department of Pathology and Pathophysiology and Department of Respiratory M, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

3Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

4Department of Respiratory and Critical Care Medicine, Regional medical center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine,, Hangzhou, China

Find articles by Cheng, H. in: PubMed | Google Scholar

1Department of Pathology and Pathophysiology and Department of Respiratory M, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

3Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

4Department of Respiratory and Critical Care Medicine, Regional medical center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine,, Hangzhou, China

Find articles by Ke, Y. in: PubMed | Google Scholar

Published July 21, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI201769.
Copyright © 2026, Jiang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 21, 2026 - Version history
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Abstract

Neddylation is highly activated in many human cancers and may serve as a therapeutic target for clinical treatment. However, it remains unclear regarding the role of neddylation in tumor angiogenesis. Here, we demonstrate that the neddylation E2 enzyme UBE2M is upregulated in tip cells and is essential for tumor vascular sprouting. We show that UBE2M-mediated neddylation of STAT1 enhances its phosphorylation and promotes the transcription of DLL4. This elevated DLL4 expression in tip cells activates Notch signaling in adjacent stalk cells, thereby maintaining the tip-stalk cell balance and ensuring organized vascular patterning. Consequently, endothelial-specific deletion of UBE2M reduces DLL4 expression, leading to excessive but non-productive sprouting due to uncontrolled tip cell formation and lack of stalk cell support, which ultimately suppresses tumor growth. Importantly, targeting endothelial neddylation potently sensitizes various tumors to anti-VEGF therapy. Together, our findings unveil UBE2M as a key regulator of angiogenic signaling and identify it as a promising anti-angiogenic target in cancer.

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  • Version 1 (July 21, 2026): In-Press Preview
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