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

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

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.

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.

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.