Spatial Transcriptomics of Microenvironmental Niches in Periodontitis and Oral Cancer

BACKGROUND: Chronic wounds and tumors share many dysregulations of stromal pathways, including hyper-inflammation, aberrant angiogenesis and fibrosis. Periodontitis (PD) lesions may be described as non-healing wounds, whereas oral squamous cell carcinomas (OSCC) are akin to over-healing wounds. Single-cell studies highlighted the cellular heterogeneities within PD and OSCC microenvironments. Spatial transcriptomics (ST) enables the profiling of global gene expression within histological tissue sections OBJECTIVE: The study's aim was to use comparative ST analyses of PD and OSCC lesions to identify cellular niches driving their pathogenesis. METHODS: ST datasets of human PD (GSE206621,N=3) and OSCC Stages I-IV (GSE208253,N=12) were obtained from GeneExpressionOmnibus. R(v4.4.1) in RStudio(v2024.09.0) was used to re-analyze datasets. Seurat(v5.1.0) was used for quality-control, individual and integrated analyses of ST and OSCC datasets, including batch-correction and visualization. SPOTlight(v1.8.0) was used for spatial voxel deconvolution into predicted cell types. CellChat(v2.1.2) was used to identify putative cell-cell interactions among spatially-adjacent voxels. SPATA2(v3.0.0) was used for histological image annotation. EnrichR was used to functionally enrich spatially/differentially expressed genes. RESULTS: Integrated spatial voxel analysis of PD and OSCC resulted in ten transcriptionally-distinct niche clusters. Functional annotation resulted in: four epithelial clusters, ranging from basal/proliferative to more differentiated cell niches; six stromal clusters, ranging from matrix-enriched/fibrotic to immune-enriched/inflammatory niches. Deconvolution showed varying contributions of several epithelial, immune and mesenchymal cell subtypes to the spatial niches, and CellChat predicted strong interactions between proliferative epithelial and fibrotic stromal niches. Histological annotation and subsequent comparative analyses revealed common enrichment of fibrotic vs non-fibrotic stromal niches in areas closer to the PD lesion and the OSCC leading edge but differential enrichment of immune-rich niches CONCLUSION (S): PD and OSCC activate adjacent stromal niches toward a common pro-fibrotic signature. Future studies will integrate additional datasets, including gingivitis and premalignant lesions to study dynamics of pathogenesis.