S100 genes drive metastasis in salivary gland carcinoma

Background High-grade salivary gland carcinoma (SGC) is an aggressive malignancy that demands a multidisciplinary treatment approach. However, its metastatic mechanisms remain poorly understood due to the rarity and heterogeneity of SGC and the lack of suitable tumor models. This study aimed to explore key oncogenic drivers of distant metastasis by comparing two SGC subtypes: salivary duct carcinoma (SDC) and adenoid cystic carcinoma (ACC). Methods We conducted a comparative analysis of SDC and ACC to identify potential oncogenes related to metastasis. A cDNA-mediated Annealing, Selection, Extension, and Ligation (DASL) assay was used to evaluate S100 gene expression in patient samples. In vivo studies were performed using orthotopic xenograft mouse models (WR21, A253, and SCA9), and functional studies employed WR21 and NIH3T3 cell lines with S100 gain- or loss-of-function to assess proliferation, migration, and invasion. Statistical analyses were applied to evaluate gene expression patterns and biological effects. Results SDC demonstrated more aggressive behavior and higher metastatic potential than ACC, accompanied by upregulation of S100 genes associated with epithelial-mesenchymal transition (EMT). SGC tumors exhibited increased expression of S100A4, S100A8, and S100A9 in both primary and metastatic lesions. Functional assays confirmed that S100 overexpression promotes EMT-related transcriptomic changes and enhances tumor cell proliferation and migration. Conditioned media from S100-expressing fibroblasts also stimulated these phenotypes, suggesting paracrine interactions in the tumor microenvironment. Conclusions S100 family proteins play a critical role in high-grade SGC progression by promoting EMT and paracrine-mediated metastasis. Hence, S100 proteins have potential as prognostic biomarkers and therapeutic targets of SGC.