PTN establishes a pro-invasive tumor-nerve microenvironment to drive perineural spread in adenoid cystic carcinoma

Abstract Adenoid cystic carcinoma is a slow-growing but highly invasive tumor that is prone to perineural invasion. At present, the molecular features of adenoid cystic carcinoma have not been fully explored, and the key cell populations and signaling pathways that regulate tumor initiation, progression, and perineural invasion remain unclear. In this study, we used single-cell RNA sequencing and spatial transcriptomics to construct a high-resolution molecular landscape of adenoid cystic carcinoma. We identified different cell subtypes and spatial cell communities, and further analyzed the spatial cellular and molecular characteristics related to tumor perineural invasion. Our results showed that pleiotrophin plays an important regulatory role in the tumor‑nerve crosstalk of adenoid cystic carcinoma. Pleiotrophin remodels the tumor stroma through cancer-associated fibroblasts and forms invasive pathways for tumor cells. In addition, it promotes demyelination and migration of Schwann cells and enhances the proliferation ability of tumor cells, which explains the molecular mechanism underlying the perineural spread of adenoid cystic carcinoma. This study explores the association between tumor microenvironment and perineural invasion, and identifies potential therapeutic targets, which may help improve the precision treatment and further research of adenoid cystic carcinoma. Trial registration Retrospectively registered.