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在一个多时间点肺转移小鼠模型中鉴定和表征 ESCC 中的转移起始细胞。

Identification and Characterization of Metastasis-Initiating Cells in ESCC in a Multi-Timepoint Pulmonary Metastasis Mouse Model.

机构信息

Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, 999077, China.

Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.

出版信息

Adv Sci (Weinh). 2024 Aug;11(30):e2401590. doi: 10.1002/advs.202401590. Epub 2024 Jun 12.

DOI:10.1002/advs.202401590
PMID:38864342
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11321633/
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 (CD44) 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

转移是食管鳞癌（ESCC）治疗的最大障碍。单细胞 RNA 测序分析被应用于研究从肺部转移的小鼠模型中分离的肺转移 ESCC 细胞，以描绘早期转移的微环境。一小部分与转移起始细胞（MICs）相似的亲本 KYSE30 细胞系（Cluster S）因其在肺部转移部位的存活和定植而被鉴定出来。Cluster S 与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 MICs。功能研究表明，MICs（CD44）表现出明显增强的细胞存活（对氧化应激和凋亡的抗性）、迁移、侵袭、干性和体内肺转移能力，而生物信息学分析显示增强的器官发育、应激反应和神经元发育，可能重塑早期转移的微环境。同时，早期转移的细胞表现出准上皮-间充质表型，以支持侵袭和锚定。4 个 MISs（CD44、S100A14、RHOD 和 TACSTD2）的多重免疫组化（mIHC）染色在 ESCC 临床样本中显示出不同的 MIS 表达评分（dMISs）可预测淋巴结转移、总生存期和癌栓形成风险。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/493b/11321633/9ab1759d243d/ADVS-11-2401590-g002.jpg
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