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Abstract：
Metastasis is the biggest obstacle to esophageal squamous cell carcinoma (ESCC) treatment. Single-cell RNA sequencing analyses are applied to investigate lung metastatic ESCC cells isolated from pulmonary metastasis mouse model at multiple timepoints to characterize early metastatic microenvironment. A small population of parental KYSE30 cell line (Cluster S) resembling metastasis-initiating cells (MICs) is identified because they survive and colonize at lung metastatic sites. Differential expression profile comparisons between Cluster S and other subpopulations identified a panel of 7 metastasis-initiating signature genes (MIS), including CD44 and TACSTD2, to represent MICs in ESCC. Functional studies demonstrated MICs (CD44high) exhibited significantly enhanced cell survival (resistances to oxidative stress and apoptosis), migration, invasion, stemness, and in vivo lung metastasis capabilities, while bioinformatics analyses revealed enhanced organ development, stress responses, and neuron development, potentially remodel early metastasis microenvironment. Meanwhile, early metastasizing cells demonstrate quasi-epithelial-mesenchymal phenotype to support both invasion and anchorage. Multiplex immunohistochemistry (mIHC) staining of 4 MISs (CD44, S100A14, RHOD, and TACSTD2) in ESCC clinical samples demonstrated differential MIS expression scores (dMISs) predict lymph node metastasis, overall survival, and risk of carcinothrombosis.
摘要：
转移是食管鳞状细胞癌（ESCC）治疗的最大障碍。应用单细胞RNA测序分析来研究在多个时间点从肺转移小鼠模型分离的肺转移性ESCC细胞,以表征早期转移性微环境。鉴定出类似于转移起始细胞(MIC)的小群亲本KYSE30细胞系(簇S),因为它们在肺转移部位存活并定殖。S簇和其他亚群之间的差异表达谱比较确定了一组7个转移起始特征基因（MIS），包括CD44和TACSTD2，代表ESCC中的中等收入国家。功能研究表明，MIC（CD44high）表现出显著增强的细胞存活率（抗氧化应激和凋亡），迁移,入侵,stemness,和体内肺转移能力，虽然生物信息学分析显示器官发育增强，应激反应，和神经元发育，可能重塑早期转移微环境。同时,早期转移细胞表现出准上皮-间质表型，以支持侵袭和锚定。4种MIS的多重免疫组织化学（mIHC）染色（CD44，S100A14，RHOD，和TACSTD2）在ESCC临床样本中证明了差异MIS表达评分（dMIS）可预测淋巴结转移，总生存率,和癌症血栓形成的风险。
