2. Academic Validation
  3. DDX5 super-enhancer promotes vasculogenic mimicry formation and metastasis in nasopharyngeal carcinoma by enhancing ADAM10 transcription

DDX5 super-enhancer promotes vasculogenic mimicry formation and metastasis in nasopharyngeal carcinoma by enhancing ADAM10 transcription

  • Cell Rep Med. 2025 Jun 17;6(6):102146. doi: 10.1016/j.xcrm.2025.102146.
Tian Xia 1,  Haimeng Yin 1,  Qingwen Zhu 1,  Kaiwen Zhang 1,  Haijing Xie 1,  Ying Shan 1,  Siyu Zhang 1,  Rui Zhu 1,  Keying Li 1,  Mengyu Miao 1,  Yingna Lu 1,  Zhefang Wang 2,  Jianmei Zhao 3,  Yiwen You 4,  Bo You 5
Affiliations

Affiliations

  • 1 Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Hospital of Nantong University, Xisi Road 20, Nantong 226019, Jiangsu Province, China; Institute of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Nantong University, Xisi Road 20, Nantong 226019, Jiangsu Province, China.
  • 2 Department of Plastic and Reconstructive Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou 310009, Zhejiang Province, China.
  • 3 Department of Pediatrics, Affiliated Hospital of Nantong University, Xisi Road 20, Nantong 226019, Jiangsu Province, China. Electronic address: zjmheart@163.com.
  • 4 Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Hospital of Nantong University, Xisi Road 20, Nantong 226019, Jiangsu Province, China; Institute of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Nantong University, Xisi Road 20, Nantong 226019, Jiangsu Province, China. Electronic address: youyiwen_ent@163.com.
  • 5 Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Hospital of Nantong University, Xisi Road 20, Nantong 226019, Jiangsu Province, China; Institute of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Nantong University, Xisi Road 20, Nantong 226019, Jiangsu Province, China. Electronic address: youbo@ntu.edu.cn.
PMID: 40412383 DOI: 10.1016/j.xcrm.2025.102146
Abstract

Anti-angiogenic therapies (AATs) exhibit limited efficacy, as most patients with Cancer inevitably develop resistance to them. In this study, data generated using a nasopharyngeal carcinoma orthotopic mouse model, combined with clinical data, reveal compensatory vasculogenic mimicry (VM) formation during AAT treatment and the association of VM with poor prognosis in nasopharyngeal carcinoma. Additionally, data-independent acquisition mass spectrometry-based proteomics shows that upregulation of a disintegrin And metalloprotease 10 (ADAM10) contributes to VM. Mechanistically, epigenetic and high-resolution chromatin interaction landscape analyses demonstrate that although ADAM10 does not interact with either the proximal or distal enhancers, DEAD-box helicase 5 (DDX5), a transcription factor of ADAM10, is regulated by long-range looping enhancer-promoter interactions. Further analyses identify transcription factors binding to critical constituents of the DDX5 super-enhancer. Ingenol mebutate, which docks excellently with DDX5, reverses ADAM10-mediated gene expression changes, thereby effectively suppressing compensatory VM formation and metastasis and improving prognosis. Collectively, these findings provide insights into the clinical application of AATs.

Keywords

ADAM10; anti-angiogenic drugs; data; data-independent acquisition; exosomes; metastasis; nasopharyngeal carcinoma; omes; super-enhancer; transcription factor; tumor microenvironment; vasculogenic mimicry.

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