Surface Proteomic Analysis Reveals the Presence of Noncanonical Cell Membrane Endoplasmic Reticulum Chaperones in High-Grade Gliomas.

High-grade gliomas (HGG) are highly aggressive tumors, which are predominately fatal for adults and pediatric patients. Identifying cancer-selective therapeutic targets remains a critical unmet need. The overexpression of endoplasmic reticulum (ER) chaperones in various cancers is well documented. Moreover, tumor cells exhibit an atypical surface expression of ER chaperones, suggesting the potential for selective targeting. Our study examined the differences in the mRNA, total protein, and surface expression levels of seven key ER chaperones, compared with those in non-neoplastic samples. Notably, a poor correlation was found between mRNA, protein, and surface protein levels, underscoring the limitations of transcriptomics alone in target discovery. We also highlight the limitations of surfaceome studies which exclude noncanonical membrane proteins, such as ectopically expressed ER chaperones, which often escape detection by conventional bioinformatic pipelines. For the first time, this study advances our understanding of the surface expression of ER chaperones in both adult and pediatric HGG. Our findings highlight the importance of surfaceome analysis in the discovery of cancer selective targets against this devastating disease.