Vitamin D Binding Protein, a Ligand of Integrin beta 1, Motivates Both Tumor Cells and Schwann Cells to Promote Perineural Invasion in Pancreatic Ductal Adenocarcinoma

Perineural invasion (PNI) is a common pathological characteristic of pancreatic ductal adenocarcinoma (PDAC), closely linked to postoperative recurrence, metastasis, and unfavorable prognosis. Nevertheless, the precise mechanisms that govern PNI in PDAC remain poorly elucidated. Here, group-specific component protein (GC) is identified as one of the most significantly upregulated genes related to PNI, primarily derived from malignant ductal cells compared to other cell types. GC knockdown attenuates PDAC cell invasiveness toward nerves, and this effect operates independently of vitamin D transport. Moreover, GC protein activates Schwann cells by inducing a dedifferentiation program, and enhances the mutual chemoattraction between PDAC cells and Schwann cells. Mechanistically, integrin β1 (ITGB1) serves as the functional receptor for GC protein in both PDAC and Schwann cells. Targeting the ITGB1-FAK signaling cascade proves effective in reducing PNI and Schwann cell activation. In KPC (Pdx-Cre; LSL-Kras^G12D+; LSL-Trp53^R172H/+) mice and orthotopic xenografts model, GC silencing and ITGB1 blockade both efficiently reduce cancer-nerve interactions and mitigate PDAC progression. Clinically, GC protein, ITGB1, and phosphorylated-FAK are positively associated with the severity of PNI in PDAC cases. Collectively, these data demonstrate that GC protein engages integrin receptor signaling to display distinct functions in cancer cells and Schwann cells, thus enabling PNI.