Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Neuro Oncol. 2023 Jul 6;25(7):1262-1274. doi: 10.1093/neuonc/noad017.
Brain metastasis (BM) is the most common intracranial malignancy causing significant mortality, and lung cancer is the most common origin of BM. However, the cellular origins and drivers of BM from lung adenocarcinoma (LUAD) have yet to be defined.
The cellular constitutions were characterized by single-cell transcriptomic profiles of 11 LUAD primary tumor (PT) and 10 BM samples (GSE131907). Copy number variation (CNV) and clonality analysis were applied to illustrate the cellular origins of BM tumors. Brain metastasis-associated epithelial cells (BMAECs) were identified by pseudotime trajectory analysis. By using machine-learning algorithms, we developed the BM-index representing the relative abundance of BMAECs in the bulk RNA-seq data indicating a high risk of BM. Therapeutic drugs targeting BMAECs were predicted based on the drug sensitivity data of cancer cell lines.
Differences in macrophages and T cells between PTs and BMs were investigated by single-cell RNA (scRNA) and immunohistochemistry and immunofluorescence data. CNV analysis demonstrated BM was derived from subclones of PT with a gain of chromosome 7. We then identified BMAECs and their biomarker, S100A9. Immunofluorescence indicated strong correlations of BMAECs with metastasis and prognosis evaluated by the paired PT and BM samples from Peking Union Medical College Hospital. We further evaluated the clinical significance of the BM-index and identified 7 drugs that potentially target BMAECs.
This study clarified possible cellular origins and drivers of metastatic LUAD at the single-cell level and laid a foundation for early detection of LUAD patients with a high risk of BM.
脑转移（BM）是最常见的颅内恶性肿瘤，导致大量死亡，而肺癌是 BM 最常见的起源。然而，肺癌脑转移（LUAD）的细胞起源和驱动因素尚未确定。
通过对 11 个 LUAD 原发肿瘤（PT）和 10 个 BM 样本的单细胞转录组谱（GSE131907）进行特征描述，应用拷贝数变异（CNV）和克隆性分析来阐明 BM 肿瘤的细胞起源。通过伪时间轨迹分析鉴定脑转移相关上皮细胞（BMAEC）。通过机器学习算法，我们开发了 BM-index 来表示大量 RNA-seq 数据中 BMAEC 的相对丰度，这表明 BM 的风险较高。基于癌细胞系的药物敏感性数据，预测了针对 BMAEC 的治疗药物。
通过单细胞 RNA（scRNA）和免疫组化及免疫荧光数据研究了 PT 和 BM 之间的巨噬细胞和 T 细胞差异。CNV 分析表明，BM 来源于 PT 的亚克隆，染色体 7 获得。然后，我们鉴定了 BMAEC 及其标志物 S100A9。免疫荧光分析表明，BMAECs 与转移和预后具有强相关性，可通过配对的北京协和医学院医院的 PT 和 BM 样本进行评估。我们进一步评估了 BM-index 的临床意义，并确定了 7 种可能靶向 BMAEC 的药物。
本研究在单细胞水平上阐明了转移性 LUAD 的可能细胞起源和驱动因素，为 LUAD 患者的早期发现提供了基础，这些患者具有 BM 高风险。
