Lrrtm3 Mediates Perineural Invasion In Adenoid Cystic Carcinoma

This study aimed to characterize the expression profile of synaptic adhesion molecule LRRTM3 and its binding partner NRXN1 in salivary adenoid cystic carcinoma (SACC), and to investigate their functional role in tumor-neural interactions and perineural invasion (PNI) pathogenesis. Systematic molecular characterization of LRRTM3/NRXN1 expression was performed across SACC cell lines and clinical specimens using qRT-PCR and multiplex immunohistochemistry. Functional validation was conducted through lentiviral-based shRNA knockdown and overexpression coupled with transwell migration and 3D matrigel invasion assays. Microphysiological modeling was established using patient-derived tumor organoids co-cultured with embryonic dorsal root ganglion (DRG) neurons enabling visualization of tumor-neural interactions. Translation validation was engineered via orthotopic PNI models in NSG mice with histomorphometric quantification of tumor cell infiltration. RNA sequencing transcriptomic profiles from 157 specimens encompassing normal salivary gland tissues and malignant counterparts revealed tissue-specific overexpression of LRRTM3 in SACC. Clinical specimens demonstrated significant LRRTM3/NRXN1 co-expression correlating with advanced TNM stage and solid histological pattern. Functional studies revealed LRRTM3 promoted tumor cell motility and induced neural plasticity through DRG-derived neurotrophic factors. In vitro co-culture models further showed that LRRTM3-overexpressing organoids promoted both tumor cell proliferation and tumor-nerve crosstalk. Consistently, in vivo analyses confirmed increased perineural invasion incidence accompanied by histological evidence. Our findings establish the LRRTM3-NRXN1 interaction as a critical mediator of PNI through neurotransmitter-driven oncogenesis. LRRTM3 could serve as a promising therapeutic target against neural invasion in SACC.