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The mechanism of the neural microenvironment controlling tumor progression during the PNI process is unclear. In the present study, we investigated the role and molecular mechanisms of nerve\u2010derived neuropeptide galanin (GAL) and its receptor (GALR2) in the regulation of PNI in SACC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Immunohistochemistry staining and clinical association studies were performed to analyze the expression of GAL and GALR2 in SACC tissues and their clinical value. Dorsal root ganglion or SH\u2010SY5Y cells were co\u2010cultured with SACC cells in vitro to simulate the interactions between the neural microenvironment and tumor cells, and a series of assays including transcriptome sequencing, Western blot, and Transwell were performed to investigate the role and molecular mechanism of GAL and GALR2 in the regulation of SACC cells. Moreover, both the in vitro and in vivo PNI models were established to assess the potential PNI\u2010specific therapeutic effects by blocking the GAL\/GALR2 axis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>GAL and GALR2 were highly expressed in SACC tissues, and were associated with PNI and poor prognosis in SACC patients (p\u2009&lt;\u20090.05). Nerve\u2010derived GAL activated GALR2 expression in SACC cells and induced epithelial\u2010to\u2010mesenchymal transition (EMT) in SACC cells. Adding human recombinant GAL to the co\u2010culture system promoted the proliferation, migration, and invasion of SACC cells significantly, but inhibited the apoptosis of SACC cells. Adding M871, a specific antagonist of GALR2, significantly blocked the above effects (p\u2009&lt;\u20090.05) and inhibited the PNI of SACC cells in vitro and in vivo (p\u2009&lt;\u20090.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study demonstrated that nerve\u2010derived GAL activated GALR2 expression, and promoted EMT in SACC cells, thereby enhancing the PNI process. Interruption of the GAL\/GALR2 axis might be a novel strategy for anti\u2010PNI therapy for SACC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.5181","type":"journal-article","created":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T05:24:46Z","timestamp":1661837086000},"page":"4496-4509","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The <scp>GAL<\/scp>\/<scp>GALR2<\/scp> axis promotes the perineural invasion of salivary adenoid cystic carcinoma via epithelial\u2010to\u2010mesenchymal transition"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0287-0662","authenticated-orcid":false,"given":"Jun","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihui","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Senior Department of Neurosurgery First Medical Center, Chinese PLA General Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, 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