Proteomic analysis reveals key differences between squamous cell carcinomas and adenocarcinomas across multiple tissues

To explore the biological insights into squamous cell carcinoma (SCC) derived from different organs, we reported a deep proteomic analysis of 333 SCCs of 17 organs and 69 adenocarcinomas (ACs) of 7 organs. Proteomic comparison between pan-SCCs and pan-ACs identifies distinguishable pivotal pathways, including keratinization, glucose metabolism, and extracellular matrix. Molecules in those pathways play consistent adverse or opposite prognostic roles in ACs and SCCs. A comparison between common and rare SCCs highlights lipid metabolism may reinforce the malignancy of rare SCCs. Proteomic clusters reveal anatomical features, and kinase-transcription factor networks indicate differential SCC initiation, while immune subtyping reveals diverse tumor microenvironments across and within diagnoses and identified potential druggable targets. HPV16 infected anogenital SCCs exhibit immune escape and higher inositol phosphate catabolic process. Furthermore, tumor-specific proteins provide candidates with differentially diagnostic values. This proteomics architecture represents a unique public resource for researchers seeking a better understanding of SCCs.