Perineural invasion in pancreatic ductal adenocarcinoma: Molecular mechanisms and clinical significance

Figure 1 Neural-invasion niche and molecular mechanisms in pancreatic ductal adenocarcinoma. Some graphic elements in the images come from the BioRender standard materials/icons library and were used in accordance with BioRender’s license. This figure illustrates the neural-immune-stromal-metabolic niche associated with perineural invasion (PNI) in pancreatic ductal adenocarcinoma (PDAC). The central anatomical interface consists of PDAC cells approaching and interacting with a peripheral nerve, together with Schwann cells, TAMs, cancer-associated fibroblasts, and extracellular matrix. Neurotrophic tumor–nerve signaling, including nerve growth factor/tropomyosin receptor kinase A - and glial cell line-derived neurotrophic factor/rearranged during transfection-related pathways, may promote tumor-nerve approximation and invasive behavior. Tumor-nerve adhesion further stabilizes contact at the interface. Schwann-cell remodeling may provide a permissive neural microenvironment for tumor-cell migration. Immune–glial signaling, including the TAMs-Schwann-cell basic fibroblast growth factor/interleukin-33 paracrine circuit, may reinforce local neural and immune remodeling. Extracellular matrix remodeling may provide a migration-permissive structural environment, whereas CAF-associated lactate metabolism and related RNA/epigenetic programs may further modify PNI-associated tumor behavior. Neural signaling represents additional communication between the nerve compartment and the surrounding TME. Arrowheads indicate the direction of the schematic relationship toward the relevant cellular or anatomical compartment. Solid connectors indicate relationships more directly supported by PDAC/PNI evidence; dashed connectors indicate predominantly preclinical, contextual, or integrative relationships. The spatial-evidence panel distinguishes direct human PNI spatial evidence[28], human neural-invasion-associated cellular states[29], and predominantly experimental neural injury/repair evidence[30]. These evidence categories indicate differences in the source and maturity of evidence rather than therapeutic efficacy. PDAC: Pancreatic ductal adenocarcinoma; CAFs: Cancer-associated fibroblasts; bFGF: Basic fibroblast growth factor; TAMs: Tumor-associated macrophages; PNI: Perineural invasion; ECM: Extracellular matrix; IL-33: Interleukin-33.