脑转移是肺腺癌（LUAD）预后不良和死亡的主要原因；然而，对 LUAD 脑转移瘤 (BM-LUAD) 的治疗策略和机制的理解仍然非常有限，特别是在蛋白质组学水平上。为了解决这个问题，我们对 49 个 BM-LUAD 肿瘤进行了综合蛋白质组和糖蛋白质组分析，揭示了该疾病的两种不同亚型：BM-S1 和 BM-S2。全外显子组测序分析显示，在 BM-S2 中更频繁地检测到 STK11 和 KEAP1 的体细胞突变以及 chr19p13.3 上的拷贝数缺失，例如 STK11、UQCR11 和 SLC25A23。在 BM-S1 肿瘤中，我们观察到 GFAP 星形胶质细胞显着浸润，GFAP、GABRA2、GABRG1 和 GAP43 蛋白水平升高以及我们的蛋白质组数据和外部空间转录组数据中星形胶质细胞特征的富集证明了这一点。相反，BM-S2 肿瘤表现出更高水平的 PD-1 免疫细胞浸润，这得到了 PD-1 和 LAG-3 基因上调的支持。这些发现表明不同的 BM-LUAD 亚型需要不同的微环境适应。此外，我们观察到亚型之间独特的糖基化模式，BM-S1 中岩藻糖基化增加，BM-S2 中唾液酸化增强，主要受到 FUT9、B4GALT1 和 ST6GAL1 等糖基化酶的影响。具体来说，在 BM-S2 中，这些唾液酸化修饰主要位于溶酶体，强调了 N-糖基化在 BM-LUAD 肿瘤进展中的关键作用。总的来说，我们的研究不仅提供了全面的多组学数据资源，而且还提供了对 BM-LUAD 有价值的生物学见解，突出了进一步研究的潜在机制和治疗靶点。版权所有 © 2024。由 Elsevier B.V. 出版。

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.Copyright © 2024. Published by Elsevier B.V.