MUC15 loss promotes perineural invasion in pancreatic cancer by activating the IGF1R/STAT3/NGF pathway

Perineural invasion (PNI) is a critical yet poorly understood feature that significantly influences the prognosis of pancreatic ductal adenocarcinoma (PDAC), a disease notorious for its dismal survival rates. Although PNI is recognized as a hallmark of pancreatic cancer, the molecular mechanisms underlying this process remain complex and incompletely defined. Recent insights into tumor-nerve interactions have highlighted the role of glycocalyx components, particularly mucin 15 (MUC15), in regulating neural invasion. In this study, we demonstrate that loss of MUC15 promotes PNI by activating the IGF1R/STAT3/NGF signaling axis. Specifically, reduced MUC15 expression weakens its interaction with IGF1R, leading to decreased receptor ubiquitination and increased phosphorylation, which in turn activates STAT3 signaling and drives NGF transcription and secretion. Loss of MUC15 also promotes epithelial-mesenchymal transition (EMT) and alters interactions with the tumor microenvironment, further facilitating neural invasion. Importantly, pharmacologic inhibition of IGF1R reverses these effects, suggesting that restoring MUC15 expression or targeting the IGF1R/STAT3-NGF axis may represent a potential therapeutic strategy to limit PNI in pancreatic cancer. These findings reveal a novel regulatory pathway connecting tumor-intrinsic signaling, EMT, and the neural microenvironment in PDAC progression.