Neuron-Derived MIF Engages VCAM1 to Fuel a Self-Amplifying CXCL8 Loop That Drives Perineural Invasion and Metastasis in Gastric Cancer

  • Adv Sci (Weinh). 2026 Jun 22:e76195. doi: 10.1002/advs.76195.
Xunjun Li  1 ,  Zhongya Zhai  1 ,  Haiyi Yu  1 ,  Renjie Qiu  1 ,  Fengyu Li  1 ,  Luxi Xiao  2 ,  Boxi Huang  1 ,  Huiying Liu  1 ,  Jiayong He  1 ,  Bowen Cai  1 ,  Jiawen Chen  1 ,  Jiang Yu  1 ,  Guoxin Li  3 ,  Tao Chen  1  4
Affiliations
  • 1. Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
  • 2. Department of Thyroid And Breast Surgery, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong Province, China.
  • 3. Cancer Center of Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China.
  • 4. Department of Gastrointestinal and Hernia Surgery, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, Jiangxi Province, China.
PMID: 42330341 DOI: 10.1002/advs.76195
Abstract

Background: Perineural invasion (PNI) is common in gastric Cancer and predicts poor prognosis, but the molecular mechanisms underlying tumour-nerve crosstalk remain unclear.

Methods: Transcriptomic data from TCGA and GEO were integrated to identify PNI regulators, with validation in surgical specimens. Mechanistic studies used tumor-neuron Transwell co-culture, siRNA/lentiviral perturbation, Western blot, immunofluorescence, ELISA, co-immunoprecipitation, and GST pull-down. Functional effects were assessed via CCK-8/Transwell assays, a sciatic nerve invasion xenograft model, and an orthotopic gastric Cancer model with neuron-specific MIF conditional knockout mice.

Results: High CXCL8/VCAM1 expression correlates with poor overall survival, distant metastasis, and is upregulated in PNI-positive tumours. Mechanistically, CXCL8 promotes neuronal MIF expression, while MIF directly binds VCAM1 and enhances tumour CXCL8 expression. VCAM1-mediated CXCL8 upregulation drives tumour proliferation and invasion. In vivo, blocking CXCL8/VCAM1 or neuron-specific MIF deletion reduces tumour growth and neural invasion.

Conclusions: A MIF-VCAM1-CXCL8 positive-feedback axis linking neural activity to gastric Cancer progression and PNI is identified, providing prognostic biomarkers and actionable therapeutic targets.

Keywords
gastric cancer; neural‐tumor interaction; perineural invasion; tumor proliferation and invasion.
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