Decoding Spatiotemporal Microenvironmental Changes in Oral Carcinogenesis

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Oral carcinogenesis is a multistage process involving epithelial hyperplasia, dysplasia, and carcinoma. Understanding the dynamic changes within the microenvironment during this process is critical for preventing disease progression. In this study, we conducted a multi-omics spatiotemporal analysis to unravel microenvironment remodeling in the carcinogenesis of oral mucosa. Our analysis identified a subset of oral epithelial progenitor cells (OEPCs) with high IGFBP2 expression. These IGFBP2 high OEPCs exhibited enhanced proliferative capacity and diminished differentiation potential, implicating their pivotal role in carcinogenesis. Additionally, we observed increasing infiltration of regulatory B cells (Bregs) during the precancerous stages. The interaction between Bregs and IGFBP2 high OEPCs was amplified via the TGF-β signaling pathway. Spatial transcriptomics confirmed the close proximity and interaction of these 2 cell types. Experiments revealed a progressive increase in IGFBP2 high OEPCs and Bregs during the precancerous stages. However, as cancer advanced, the infiltration of Bregs stagnated and even declined. This finding suggests that while tumor initiation and progression represent a continuous process, the regulatory mechanisms involved may not remain entirely the same across these stages. Consequently, focusing exclusively on the cancerous stage risks overlooking abnormalities that emerge during the precancerous phase. In conclusion, this study integrates multi-omics spatiotemporal data to uncover the evolution of the microenvironment during the carcinogenesis of oral mucosa. Specifically, Bregs were observed to gradually accumulate and spatially associate with IGFBP2 high OEPCs via the TGF-β signaling pathway, correlating with a disrupted balance between proliferation and differentiation, which may contribute to triggering malignancy.

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