Prominent crosstalks between perineural invasion and immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma

Figure 2 Activated Schwann cells serve as central orchestrators of perineural invasion in pancreatic ductal adenocarcinoma. They secrete neurotrophins including nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor to drive neural remodeling, while matrix metalloproteinase-2, matrix metalloproteinase-9, and L1-cell adhesion molecule degrade the perineural extracellular matrix to facilitate tumor cell entry. Schwann cell-derived CCL2, CXCL12, and interleukin-6 further recruit immune cells and guide tumor cell migration along nerve trunks toward the celiac plexus. NGF: Nerve growth factor; BDNF: Brain-derived neurotrophic factor; GDNF: Glial cell line-derived neurotrophic factor; NT-3: Neurotrophin-3; IL: Interleukin; TGF-β: Transforming growth factor-β; TNF-α: Tumor necrosis factor-α; PNI: Perineural invasion; ECM: Extracellular matrix; MMP: Matrix metalloproteinase; CAM: Cell adhesion molecule.