2. Academic Validation
  3. Endothelial PDLIM5 promotes tip cell filopodia formation and tumor angiogenesis by regulating ACTN1/ACTN4-dependent actin bundling

Endothelial PDLIM5 promotes tip cell filopodia formation and tumor angiogenesis by regulating ACTN1/ACTN4-dependent actin bundling

  • Nat Commun. 2026 Jan 28;17(1):2103. doi: 10.1038/s41467-026-68765-x.
Zhiyong Xu # 1 2,  Yueli Shi # 1 2,  Yan Yang # 1 3,  Bufu Tang # 4,  Jiangnan Zhao 1 2,  Mingshu Xiao 1 2,  Sujing Jiang 1,  Xinyuan Jiang 1 2,  Nueraili Maihemuti 1 2,  Kaiyue Zhang 1 2,  Huan Wang 1,  Yun Xu 1 2,  Yuchao Sun 1 2,  Xiuying Chen 5,  Peng Xiao 6,  Haiyan Xu 7,  Hongqiang Cheng 8,  Kai Wang 9 10
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China.
  • 2 Zhejiang Key Laboratory of Precision Diagnosis and Treatment for Lung Cancer, Yiwu, China.
  • 3 Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 5 Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
  • 6 Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 7 Department of Biobank, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 8 Department of Pathology and Pathophysiology and Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 9 Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China. [email protected].
  • 10 Zhejiang Key Laboratory of Precision Diagnosis and Treatment for Lung Cancer, Yiwu, China. [email protected].
  • # Contributed equally.
PMID: 41605926 DOI: 10.1038/s41467-026-68765-x
Abstract

Filopodia formation by tumor endothelial cells (TECs) is critical for tip cell-guided sprouting angiogenesis and tumor growth. However, the cytoskeletal organization that underlies this process remains elusive. Here, we demonstrates that TECs highly express actin-binding genes, with PDZ and LIM domain 5 (PDLIM5), a cytoskeletal protein, significantly upregulated in TECs and correlated with poor patient survival. Endothelial-specific deletion of Pdlim5 inhibits sprouting angiogenesis by disrupting filopodia formation through its interaction with actinin-1/actinin-4 (ACTN1/ACTN4) via its S593/F596 residues, promoting filamentous actin (F-actin) bundling. Pdlim5 knockout not only reduces tumor growth but also normalizes tumor vasculature, alleviates hypoxia, and enhances immunotherapy and chemotherapy responses. These findings highlight the PDLIM5's role in facilitating tumor angiogenesis via ACTN1/ACTN4-mediated F-actin bundling and tip cell filopodia formation, providing mechanistic insights that may inform future therapeutic strategies targeting this pathway.

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