Decoding Schwann cell activation in pancreatic cancer neural invasion by mimicking nerve injury responses and using spatial transcriptomics

Perineural invasion (PNI) is a critical neuropathic change in pancreatic cancer, driven by cancer-nerve interactions, where Schwann cells (SC) undergo reprogramming similar to nerve injury, promoting tumor spread. Despite this, the molecular mechanisms underlying SC activation and their involvement in extrapancreatic PNI remain poorly understood. In this study, we drew an analogy between the process of PNI and nerve injury, identifying six nerve injury-related genes (ARRDC4, ATF3, CBFB, NAV2, SNTB1, and TOX) that are highly expressed in SC and implicated in PNI. To certify the role of the selected six genes in neural invasion, the expression of these genes in N008 were knockdown by siRNA.After knocking down the expression of these six genes in N008 cells and performing RNA sequencing, it was found that the knockdown of these genes was associated with the activation of neural pathways, such as axon regeneration, Schwann cell differentiation, axonogenesis, and neurogenesis ,suggesting that these genes likely influence the functions of periphery nervous system.