Integrated analyses of multi-omic data derived from paired primary lung cancer and brain metastasis reveal the metabolic vulnerability as a novel therapeutic target

作者：Hao Duan, Jianlan Ren, Shiyou Wei, Zhenyu Yang, Chuan Li, Zhenning Wang, Meichen Li, Zhi Wei, Yu Liu, Xiuqi Wang, Hongbin Lan, Zhen Zeng, Maodi Xie, Yuan Xie, Suwen Wu, Wanming Hu, Chengcheng Guo, Xiangheng Zhang, Lun Liang, Chengwei Yu, Yanhao Mou, Yanhao Mou, Yu Jiang, Houde Li, Eric Sugarman, Rebecca A. Deek, Zexin Chen, Tao Li, Yaohui Chen, Maojin Yao, Likun Chen, Lunxu Liu, Gao Zhang, Yonggao Mou, Yonggao Mou · 发表于：Genome Medicine · 年份：2024 · DOI：10.1186/s13073-024-01410-8 · 被引用次数：36 · 研究领域：Lung Cancer Treatments and Mutations、Lung Cancer Research Studies、Brain Metastases and Treatment

BACKGROUND: Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A deep understanding of molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. METHODS: Here, we performed integrated analyses of genomic, transcriptomic, proteomic, metabolomic, and single-cell RNA sequencing data which were derived from a total number of 154 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels. RESULTS: We uncovered that LC-BrMs exhibited a significantly greater intra-tumor heterogeneity. We also observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TTN, TP53, MUC16, LRP1B, RYR2, and EGFR. In addition, the genome-wide landscape of somatic copy number alterations was similar between primary lung cancers and LC-BrM lesions. Nevertheless, several regions of focal amplification were significantly enriched in LC-BrMs, including 5p15.33 and 20q13.33. Intriguingly, integrated analyses of transcriptomic, proteomic, and metabolomic data revealed mitochondrial-specific metabolism was activated but tumor immune microenvironment was suppressed in LC-BrMs. Subse...