Multidimensional Proteomic Landscape Reveals Distinct Activated Pathways Between Human Brain Tumors

Abstract Brain metastases (BrMs) and gliomas are two typical human brain tumors with high incidence of mortalities and distinct clinical challenges, yet the understanding of these two types of tumors remains incomplete. Here, a multidimensional proteomic landscape of BrMs and gliomas to infer tumor‐specific molecular pathophysiology at both tissue and plasma levels is presented. Tissue sample analysis reveals both shared and distinct characteristics of brain tumors, highlighting significant disparities between BrMs and gliomas with differentially activated upstream pathways of the PI3K‐Akt signaling pathway that have been scarcely discussed previously. Novel proteins and phosphosites such as NSUN2, TM9SF3, and PRKCG_S330 are also detected, exhibiting a high correlation with reported clinical traits, which may serve as potential immunohistochemistry (IHC) biomarkers. Moreover, tumor‐specific altered phosphosites and glycosites on FN1 are highlighted as potential therapeutic targets. Further validation of 110 potential noninvasive biomarkers yields three biomarker panels comprising a total of 19 biomarkers (including DES, VWF, and COL1A1) for accurate discrimination of two types of brain tumors and normal controls. In summary, this is a full‐scale dataset of two typical human brain tumors, which serves as a valuable resource for advancing precision medicine in cancer patients through targeted therapy and immunotherapy.