Perineural invasion (PNI) has significant implications for the prognosis of patients with head and neck squamous cell carcinoma (HNSCC). Lissencephaly-1 (LIS1) plays a crucial role in neural development and is highly expressed in HNSCC, showing a positive correlation with tumor invasion. However, the precise role of LIS1 in PNI and its underlying molecular mechanisms are not well understood.

The study employed bioinformatics analysis and immunohistochemistry to investigate the gene expression of LIS1 in HNSCC tissues. Transwell assays, wound healing assays, and co-culture models were used to evaluate the PNI capacity of HNSCC cells in vitro. A microfluidic chip was designed to study the interactions between the tumor and Schwann cells. RNA sequencing analysis provided insights into the signaling pathways involved in LIS1. Mechanistic investigations were performed using RT-qPCR and Western blotting. Additionally, a murine sciatic nerve invasion model was established to assess the effects of LIS1 on tumor invasion and PNI in vivo.

Analysis of the TIMER and GEPIA2 databases revealed elevated levels of LIS1 mRNA in HNSCC tissues compared to those in adjacent normal tissues. Clinicopathological evaluation confirmed that LIS1 expression was enriched in the tumor cytoplasm and positively correlated with PNI. HNSCC cells overexpressing LIS1 demonstrated enhanced PNI capacity. Co-culture experiments revealed that LIS1 expression in tumor cells stimulated the proliferation and migration of SCs. RNA sequencing analysis identified the regulatory effects of LIS1 on PHGDH, PSAT1, and PSPH, which activate the serine pathway. Subsequent investigations demonstrated that serine, acting on Schwann cells through the NMDAR/AKT signaling pathway, promotes tumor PNI. In vivo experiments using nude mice supported the role of LIS1 in promoting the PNI capacity through the serine pathway.

Our findings indicate that LIS1 expression in HNSCC is pivotal for facilitating communication between tumor cells and Schwann cells through the serine/NMDAR/AKT axis, thereby promoting perineural invasion of HNSCC. Our study identified LIS1 as a potential predictive marker of perineural invasion and underscored its significance as a therapeutic target for HNSCC treatment.