2. Academic Validation
  3. Scaffolding Protein ENH Promotes Tumor Angiogenesis and Growth Through Macrophage Recruitment and Polarization

Scaffolding Protein ENH Promotes Tumor Angiogenesis and Growth Through Macrophage Recruitment and Polarization

  • Adv Sci (Weinh). 2025 Jun 19:e16476. doi: 10.1002/advs.202416476.
Yueli Shi 1 2,  Zhiyong Xu 1 2,  Huan Wang 3,  Bufu Tang 4,  Nueraili Maihemuti 1 2,  Xinyuan Jiang 1 2,  Xiuying Chen 5,  Mingshu Xiao 1 2,  Sujing Jiang 6,  Yun Xu 1 2,  Peng Xiao 7,  Jiangnan Zhao 1 2,  Kaiyue Zhang 1 2,  Mengshu Li 1 2,  Kai Wang 1 2
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Center for Oncology Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
  • 2 Zhejiang Key Laboratory of Precision Diagnosis and Treatment for Lung Cancer, Yiwu, 322000, China.
  • 3 Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China.
  • 4 Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, 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, 322000, China.
  • 6 Department of Gastroenterology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 7 Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
PMID: 40536254 DOI: 10.1002/advs.202416476
Abstract

Angiogenesis is vital for tumor growth and metastasis, with tumor-associated macrophages (TAMs) being key pro-angiogenic cells recruited by tumor-secreted chemokines. High levels of TAMs contribute to tumor progression and antiangiogenic therapy resistance. Therefore, intensive study of the regulatory mechanisms of TAMs recruitment during tumor development is important for the discovery of new antitumor and antiangiogenic therapeutic strategies. Here, we found that in lung adenocarcinoma (LUAD), ENH levels positively correlated with microvessel density and TAMs infiltration. Further exploration revealed that ENH promoted LUAD angiogenesis and growth by stimulating TAMs recruitment and M2 polarization. Mechanistically, ENH in LUAD induced YAP nuclear aggregation to promote CCL5 transcription, thereby increasing monocyte chemotaxis and ultimately increasing TAMs infiltration and M2 polarization. Besides, we found that ENH interacted with YAP through LIM domains, which significantly triggered the formation of YAP-KPNA2 complexes. Consequently, YAP is imported into the nucleus by KPNA2 and then promoted CCL5 transcription. Notably, ENH knockdown also significantly increased the chemosensitivity. Together, ENH functions in LUAD cells to mediate macrophage infiltration and M2 polarization, which in turn promotes tumor angiogenesis and growth, and targeting ENH offers a promising target for antiangiogenic therapy through immune modulation.

Keywords

ENH protein; YAP signaling; angiogenesis; lung adenocarcinoma; tumor‐associated macrophages.

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