Spatio‐Temporal Proteomic Landscape Reveals Early Warning Signals of Esophageal Squamous Cell Carcinoma Progression

Esophageal squamous cell carcinoma (ESCC) remains a lethal malignancy lacking reliable biomarkers for precancerous lesion monitoring and intervention. In this study, formalin-fixed, paraffin-embedded archived tissue biopsies from 134 individuals across two cohorts are collected, spanning five stages of ESCC progression. Laser capture microdissection is employed to isolate the epithelial lesion (L) and the adjacent non-lesion (N) tissues. Proteomic profiling reveals a comprehensive spatio-temporal landscape of ESCC progression, encompassing 4461 proteins. Dynamic network biomarker analysis indicates moderate dysplasia (MOD) as the critical turning stage, warranting clinical attention. A seven-protein diagnostic panel (CCDC86, GBP6, PDCD6IP, C19orf53, SF3A3, GMPPB, ARPC5) with an area under the curve (AUC) of 0.956 achieves superior early detection, and the key signatures are validated by immunohistochemistry in an independent cohort. Functional validation using malignantly transformed HET-1A cells, ESCC cells, and mouse xenograft models identifies GBP6 as a novel target: DNA damage-induced progressive loss of GBP6 promotes ESCC progression by accelerating cell cycle and inducing epithelial-mesenchymal transition. Critically, PARP1 inhibition rescues GBP6 loss by suppressing TP63 and prevents ESCC progression. Overall, this study provides a systematic proteomic atlas of ESCC progression, identifies MOD as a pivotal clinical decision point, and proposes PARP1-TP63-GBP6 axis targeting as a novel intervention strategy.