Li Pei-Heng, Zhang Xin, Yan Huayun, Xia Xuyang, Deng Yiqi, Miao Qiang, Luo Yiqiao, Liu Guihong, Luo Han, Zhang Yan, Xu Heng, Jiang Lili, Li Zhi-Hui, Shu Yang
Division of Thyroid Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China.
Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Transl Lung Cancer Res. 2024 May 31;13(5):965-985. doi: 10.21037/tlcr-24-118. Epub 2024 May 29.
Tumor metastasis commonly affects pleura in advanced lung cancer and results in malignant pleural effusion (MPE). MPE is related to poor prognosis, but without systematic investigation on different cell types and their crosstalk at single cell resolution.
We conducted single-cell RNA-sequencing (scRNA-seq) of lung cancer patients with pleural effusion. Next, our data were integrated with 5 datasets derived from individuals under normal, non-malignant disease and lung carcinomatous conditions. Mesothelial cells were re-clustered and their interactions with epithelial cells were comprehensively analyzed. Taking advantage of inferred ligand-receptor pairs, a prediction model of prognosis was constructed. The co-culture of mesothelial cells and malignant epithelial cells and RNA-seq was performed. Epidermal growth factor receptor () antagonist cetuximab was utilized to prevent the lung cancer cells' invasiveness. Spatial distribution of cells in lung adenocarcinoma patients' samples were also analyzed to validate our findings.
The most distinctive transcriptome profiles between tumor and control were revealed in mesothelial cells, which is the predominate cell type of pleura. Five subtypes were divided, including one predominately identified in MPE which was characterized by enriched cancer-related pathways (e.g., cell migration) along evolutionary trajectory from normal mesothelial cells. Cancer-associated mesothelial cells (CAMCs) exhibited varied interactions with different subtypes of malignant epithelial cells, and multiple ligands/receptors exhibited significant correlation with poor prognosis. Experimentally, mesothelial cells can increase the migration ability of lung cancer cells through co-culturing. was the only affected gene in cancer cells that exhibited interaction with mesothelial cells and was associated with poor prognosis. Using antagonist cetuximab prevented the lung cancer cells' increased invasiveness caused by mesothelial cells. Moreover, epithelial mitogen ()- interaction was supported through spatial distribution analysis, revealing the significant proximity between EPGN mesothelial cells and EGFR epithelial cells.
Our findings highlighted the important role of mesothelial cells and their interactions with cancer cells in pleural metastasis of lung cancer, providing potential targets for treatment.
肿瘤转移在晚期肺癌中常累及胸膜并导致恶性胸腔积液（MPE）。MPE与预后不良相关，但尚未在单细胞分辨率下对不同细胞类型及其相互作用进行系统研究。
我们对伴有胸腔积液的肺癌患者进行了单细胞RNA测序（scRNA-seq）。接下来，我们将数据与来自正常、非恶性疾病和肺癌患者的5个数据集进行整合。对间皮细胞进行重新聚类，并全面分析它们与上皮细胞的相互作用。利用推断出的配体-受体对，构建了预后预测模型。进行了间皮细胞与恶性上皮细胞的共培养及RNA测序。使用表皮生长因子受体（EGFR）拮抗剂西妥昔单抗来预防肺癌细胞的侵袭性。还分析了肺腺癌患者样本中细胞的空间分布以验证我们的发现。
在间皮细胞中揭示了肿瘤与对照之间最显著的转录组图谱，间皮细胞是胸膜的主要细胞类型。划分出了五个亚型，其中一个主要在MPE中被鉴定出来，其特征是沿着从正常间皮细胞的进化轨迹富集了与癌症相关的通路（如细胞迁移）。癌症相关间皮细胞（CAMCs）与不同亚型的恶性上皮细胞表现出不同的相互作用，多种配体/受体与预后不良显著相关。实验表明，间皮细胞可通过共培养增加肺癌细胞的迁移能力。EGFR是癌细胞中唯一受影响的基因，它与间皮细胞相互作用并与预后不良相关。使用EGFR拮抗剂西妥昔单抗可预防间皮细胞导致的肺癌细胞侵袭性增加。此外，通过空间分布分析支持了上皮有丝分裂原（EPGN）-EGFR相互作用，揭示了EPGN间皮细胞与EGFR上皮细胞之间的显著接近性。
我们的研究结果突出了间皮细胞及其与癌细胞的相互作用在肺癌胸膜转移中的重要作用，为治疗提供了潜在靶点。
