Integrated Proteomic and Glycoproteomic Analysis Reveals Heterogeneity and Molecular Signatures of Brain Metastases from Lung Adenocarcinomas

蛋白质组学 生物 腺癌 病理 计算生物学 癌症研究 医学 内科学 癌症 生物化学 遗传学 基因
作者
Yang Zhao,Dainan Zhang,Bo Meng,Yong Zhang,Shunchang Ma,Jiaming Zeng,Xi Wang,Tao Peng,Xiaoyun Gong,Rui Zhai,Lianhua Dong,You Jiang,Xinhua Dai,Xiang Fang,Jia Wang
出处
期刊:Cancer Letters [Elsevier]
卷期号:: 217262-217262
标识
DOI:10.1016/j.canlet.2024.217262
摘要

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.
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