Identifying New Contributors to Brain Metastasis in Lung Adenocarcinoma: A Transcriptomic Meta-Analysis

SIMPLE SUMMARY: Lung cancer patients have a high mortality risk due to brain metastases (BM). Understanding the molecular changes that contribute to BM is essential to identify potential therapeutic targets. Previous research has focused on primary tumor alterations, with less attention given to BM. This study examined a unique transcriptomic dataset assembled from previously reported RNA-seq, microarray, and single-cell analyses of BM samples from lung adenocarcinoma (LUAD) patients in pursuit of gaining a better understanding of the molecular landscape of BM. We found that dendritic cells and neutrophils were present in LUAD-BM, which could contribute to an immunosuppressive tumor microenvironment. The expression levels of 102 genes were altered, with CD69 and GZMA identified as ‘hub’ genes, which could play a role in LUAD-BM. BM-specific gene expression was also observed, further supporting the presence of an immunosuppressive tumor microenvironment. ABSTRACT: Lung tumors frequently metastasize to the brain. Brain metastasis (BM) is common in advanced cases, and a major cause of patient morbidity and mortality. The precise molecular mechanisms governing BM are still unclear, in part attributed to the rarity of BM specimens. In this work, we compile a unique transcriptomic dataset encompassing RNA-seq, microarray, and single-cell analyses from BM samples obtained from patients with lung adenocarcinoma (LUAD). By integrating this comprehensive dataset, we aimed to enhance understanding of the molecular landscape of BM, thereby facilitating the identification of novel and efficient treatment strategies. We identified 102 genes with significantly deregulated expression levels in BM tissues, and discovered transcriptional alterations affecting the key driver ‘hub’ genes CD69 (a type II C-lectin receptor) and GZMA (Granzyme A), indicating an important role of the immune system in the development of BM from primary LUAD. Our study demonstrated a BM-specific gene expression pattern and revealed the presence of dendritic cells and neutrophils in BM, suggesting an immunosuppressive tumor microenvironment. These findings highlight key drivers of LUAD-BM that may yield therapeutic targets to improve patient outcomes.