Pre-metastatic niche in oral squamous cell carcinoma: Insights from a transcriptomic meta-analysis

Primary tumors can precondition a pre-metastatic niche, promoting the colonization of circulating neoplastic cells and influencing the secondary tumor microenvironment. Nevertheless, the mechanisms underlying the formation of this niche, as well as perineural invasion in oral squamous cell carcinoma (OSCC), are not well-elucidated. The study aims to identify differentially expressed genes (DEGs) and related pathways associated with pre-metastatic niche and perineural invasion in OSCC. We evaluated metastatic and non-metastatic primary tumor samples, healthy oral tissues, OSCC samples, metastatic lymph nodes from patients with OSCC, and normal lymph node samples. The GEO2R tool was applied to identify mRNAs differentially expressed between tissues exhibiting features of a pre-metastatic niche and normal tissue samples, including selected non-metastatic and metastatic OSCC samples. We also performed an analysis of perineural invasion-negative and perineural invasion-positive tumor samples. Our data revealed that SERPINE1, SPP1, CALCA, and MMP13 genes were upregulated. These upregulated genes are associated with several cancer-related pathways, while downregulated genes are mainly associated with immune responses, axon guidance, and the neurotrophin signaling pathway. Given the upregulation of the circadian rhythm pathway in metastatic lymph nodes, we also performed a correlation analysis that allows users to compute function-specific parameters, with resulting figures dynamically displayed to conveniently access the tumor’s immunological, clinical, and genomic features. Downregulation of the circadian rhythm gene PER3 and upregulation of Bhlhe40 were associated with poor survival outcomes. In conclusion, we postulate that during lymph node invasion, OSCCs activate axonal guidance genes, such as SERPENE1, L1AM, CXCR4, and SPP1. As neoplastic cells establish themselves, circadian rhythm genes are upregulated, contributing to immune evasion and promoting tumor growth.