Integrated proteomic and glycoproteomic analysis reveals heterogeneity and molecular signatures of brain metastases from lung adenocarcinomas

Brain metastasis is a major cause of poor prognosis and death in lung adenocarcinoma (LUAD); however, the understanding of therapeutic strategies and mechanisms for brain metastases from LUAD (BM-LUAD) remains notably limited, especially at the proteomics levels. To address this issue, we conducted integrated proteomic and glycoproteomic analyses on 49 BM-LUAD tumors, revealing two distinct subtypes of the disease: BM-S1 and BM-S2. Whole exome sequencing analysis revealed that somatic mutations in STK11 and KEAP1, as well as copy number deletions on chr19p13.3, such as STK11, UQCR11, and SLC25A23, were more frequently detected in BM-S2. In BM-S1 tumors, we observed significant infiltration of GFAP + astrocytes, as evidenced by elevated levels of GFAP, GABRA2, GABRG1 and GAP43 proteins and an enrichment of astrocytic signatures in both our proteomic data and external spatial transcriptomic data. Conversely, BM-S2 tumors demonstrated higher levels of PD-1 immune cell infiltration, supported by the upregulation of PD-1 and LAG-3 genes. These findings suggest distinct microenvironmental adaptations required by the different BM-LUAD subtypes. Additionally, we observed unique glycosylation patterns between the subtypes, with increased fucosylation in BM-S1 and enhanced sialylation in BM-S2, primarily affected by glycosylation enzymes such as FUT9, B4GALT1, and ST6GAL1. Specifically, in BM-S2, these sialylation modifications are predominantly localized to the lysosomes, underscoring the critical role of N-glycosylation in the tumor progression of BM-LUAD. Overall, our study not only provides a comprehensive multi-omic data resource but also offers valuable biological insights into BM-LUAD, highlighting potential mechanisms and therapeutic targets for further investigation. Identification of Two Distinct Subtypes of BM-LUAD.Our study revealed two distinct molecular subtypes of BM-LUAD, BM-S1 and BM-S2, through integrated proteomic and glycoproteomic analyses of 49 tumors. This differentiation provides a deeper understanding of the heterogeneity within BM-LUAD, which is crucial for developing targeted therapies. Potential Targets: STK11 and chr19p13.3 in BM-LUAD Therapy.Our analysis identified frequent mutations and deletions in STK11 and chr19p13.3 in BM-S2, which impact tumor proliferation and mitochondrial function.Targeting these genetic alterations may be essential for effective therapies in these specific tumor profiles. Microenvironmental Adaptations in BM-L