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

Table 1 Mechanistic layers and evidence boundaries of perineural invasion in pancreatic ductal adenocarcinoma

Mechanistic layer	Representative axis/process	Cellular context and biological role	Evidence level and translational implication	Key references
Neurotrophic tumor-nerve convergence	NGF-TrkA signaling	Context: Tumor-nerve interface	Evidence: Review-level synthesis	[8]
		Role: Associated with chemotaxis, adhesion, and invasive behavior within reciprocal tumor–nerve signaling	Translation: Mechanistic target for further study
Neurotrophic tumor-nerve convergence	GDNF-RET signaling	Context: Experimental pancreatic cancer models	Evidence: Experimental pancreatic cancer evidence	[13]
		Role: Reported to engage CDC42/RHOA cytoskeletal regulation and SRC/GRB2-associated invadopodia formation	Translation: Preclinical therapeutic rationale
Schwann-cell remodeling	Injury-responsive Schwann-cell redistribution and neural remodeling	Context: Schwann cells at tumor-associated peripheral nerves	Evidence: Review-level synthesis	[14]
		Role: May provide a permissive neural-remodeling context for tumor-cell migration without establishing a single recruitment direction	Translation: Mechanistic process requiring direct validation
Immune-glial feedback	TAM-Schwann bFGF/IL-33 paracrine feedback	Context: Tumor-associated macrophages and Schwann cells	Evidence: Experimental pancreatic cancer evidence	[9]
		Role: Mechanistic evidence suggests reciprocal activation, macrophage recruitment, and M2-like polarization in the perineural niche	Translation: Candidate target-discovery pathway; clinical relevance requires validation
Tumor-nerve adhesion	L1CAM-associated adhesion and metalloproteinase signaling	Context: Tumor-nerve interface	Evidence: Experimental pancreatic cancer evidence	[15]
		Role: Associated with adhesive interactions and metalloproteinase-linked invasive behavior	Translation: Mechanistic target for further study
Extracellular-matrix remodeling	LAMA3 and extracellular-matrix organization	Context: Perineural tumor–stromal matrix	Evidence: Human pancreatic cancer association	[8,16]
		Role: LAMA3 expression and matrix reorganization are associated with perineural invasion and adverse pathological features; causality is not established	Translation: Association requiring validation
Metabolic regulation	CAF-associated high-lactate microenvironment	Context: Cancer-associated fibroblast-rich tumor microenvironment	Evidence: Experimental pancreatic cancer evidence	[11]
		Role: High lactate is linked to epigenetic regulation of perineural-invasion-related programs, including L1CAM and SLIT1	Translation: Mechanistic pathway for further study
Non-coding RNA regulation	CAF-derived circKLHL24-Sec31A/miR-615-5p-CXCL12 regulation	Context: Cancer-associated fibroblasts and pancreatic cancer cells	Evidence: Experimental pancreatic cancer evidence	[17]
		Role: Reported to regulate Sec31A and miR-615-5p/CXCL12 signaling in perineural-invasion-related phenotypes	Translation: Preclinical target-discovery pathway
RNA modification	Lactate-NSUN2-m5C-CDCP1/STC1 regulation	Context: High-lactate microenvironment and pancreatic cancer cells	Evidence: Experimental pancreatic cancer evidence	[18]
		Role: Lactate-associated NSUN2 modification is linked to m5C-dependent stabilization of CDCP1 and STC1 transcripts and perineural-invasion-related phenotypes	Translation: Candidate metabolic-epigenetic pathway requiring validation
Neural immune regulation	Acetylcholine-M3R/HDAC1-CCL5 signaling	Context: Nerve-associated cholinergic signaling, pancreatic cancer cells, and local immune context	Evidence: Human pancreatic cancer mechanistic evidence	[10]
		Role: Reported to alter CCL5-dependent CD8+ T-cell recruitment and function in mechanistic models	Translation: Preclinical therapeutic rationale; no established clinical efficacy
Neural signaling and drug-response phenotype	Neurotensin-NTSR1-Akt signaling	Context: Neuron-tumor signaling in experimental pancreatic cancer	Evidence: Experimental pancreatic cancer evidence	[19]
		Role: Associated with invasiveness and a gemcitabine-resistance phenotype in experimental models	Translation: Preclinical therapeutic rationale
Pain-related neural signaling	NGF-related sensory sensitization and nociceptor signaling	Context: Tumor–sensory nerve interface	Evidence: Review-level synthesis	[5,7,22]
		Role: Supports a symptom-relevant sensitization pathway but does not establish a single cause of pain or a direct relation between invasion severity and pain intensity	Translation: Symptom-relevant mechanism requiring direct validation

Evidence levels describe the maturity and directness of the cited evidence and do not imply therapeutic efficacy. NGF: Nerve growth factor; TrkA: Tropomyosin receptor kinase A; GDNF: Glial cell line-derived neurotrophic factor; RET: Rearranged during transfection; TAM: Tumor-associated macrophage; bFGF: Basic fibroblast growth factor; IL-33: Interleukin-33; L1CAM: L1 cell adhesion molecule; LAMA3: Laminin subunit alpha 3; CAF: Cancer-associated fibroblast; circKLHL24: Circular RNA derived from KLHL24; Sec31A: SEC31 homolog A; miR-615-5p: MicroRNA-615-5p; CXCL12: C-X-C motif chemokine ligand 12; NSUN2: RNA methyltransferase NSUN2; m5C: 5-methylcytosine; CDCP1: CUB domain-containing protein 1; STC1: Stanniocalcin 1; M3R: Muscarinic acetylcholine receptor M3; HDAC1: Histone deacetylase 1; CCL5: C-C motif chemokine ligand 5; NTSR1: Neurotensin receptor 1; Akt: Protein kinase B.