Spatial transcriptomics analysis and functional studies unveil molecular hallmarks of cervical squamous cell cancer tumorigenesis

"Background: Cervical cancer (CC) ranks as the fourth most prevalent malignancy among females globally, with cervical squamous cell carcinoma (CSCC) representing about 75% of CC cases. Understanding the stepwise progression of CSCC is paramount for tailoring strategies for early diagnosis and optimal clinical treatment. This study was to reveal the transcriptional and immunologic changes and identify clinically relevant biomarkers essential for the detection and advancement of precision medicine in the transition from normal cervical tissue to CSCC.Results: Digital spatial profiling (DSP) on pT1 CSCCs within the epithelial and stromal compartments across various histological regions encompassing normal cervix, low- and high-grade squamous intraepithelial lesions, and cancer, revealed the spatial transcriptional reprogramming and dynamic cell signaling pathways that govern the progression of CSCC. DSP and immunohistochemistry results revealed an elevated infiltration of macrophage and T regulatory cell populations from normal cervix through lesions to cancer. Additionally, a gradual decline in SPINK5 expression and an increase in SPP1 expression were identified along the spectrum of CSCC progression. In vitro and in vivo functional studies demonstrated that the downregulation of SPINK5 accelerates CSCC progression and the addition of recombinant human SPP1 promoted the malignant phenotypes of SiHa and CaSki cells, including increased cell proliferation, migration, invasion, angiogenesis, and inhibited cell apoptosis. Collectively, SPINK5 and SPP1 emerge as potential biomarkers indicative of the predisposition to CSCC tumorigenesis.Conclusions: We explored the molecular and immunological signatures of CSCC tumorigenesis and pinpointed potential biomarkers essential for early detection. This study serves as a significant repository offering insights into the onset and progression of CSCC, consequently aiding in refining diagnostic accuracy and crafting optimal treatment strategies."