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Single\u2010cell 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\u2010initiating 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\u2010initiating signature genes (MIS), including CD44 and TACSTD2, to represent MICs in ESCC. Functional studies demonstrated MICs (CD44<jats:sup>high<\/jats:sup>) 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\u2010epithelial\u2010mesenchymal 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.<\/jats:p>","DOI":"10.1002\/advs.202401590","type":"journal-article","created":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T06:11:09Z","timestamp":1718172669000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification and Characterization of Metastasis\u2010Initiating Cells in ESCC in a Multi\u2010Timepoint Pulmonary Metastasis Mouse Model"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5034-7067","authenticated-orcid":false,"given":"Ching Ngar","family":"Wong","sequence":"first","affiliation":[{"name":"Department of Clinical Oncology Centre for Cancer Medicine Li Ka Shing Faculty of Medicine The University of Hong 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