Metastasis-initiating cells with stem-like properties drive cancer lethality, yet their origins and relationship to primary-tumor-initiating stem cells are not known. We show that L1CAM⁺ cells in human colorectal cancer (CRC) have metastasis-initiating capacity, and we define their relationship to tissue regeneration. L1CAM is not expressed in the homeostatic intestinal epithelium, but is induced and required for epithelial regeneration following colitis and in CRC organoid growth. By using human tissues and mouse models, we show that L1CAM is dispensable for adenoma initiation but required for orthotopic carcinoma propagation, liver metastatic colonization and chemoresistance. L1CAM^high cells partially overlap with LGR5^high stem-like cells in human CRC organoids. Disruption of intercellular epithelial contacts causes E-cadherin–REST transcriptional derepression of L1CAM, switching chemoresistant CRC progenitors from an L1CAM^low to an L1CAM^high state. Thus, L1CAM dependency emerges in regenerative intestinal cells when epithelial integrity is lost, a phenotype of wound healing deployed in metastasis-initiating cells.

具有干细胞样特性的转移起始细胞驱动癌症致死率，但它们的起源和与原发性肿瘤起始干细胞的关系尚不清楚。我们表明人类结直肠癌 (CRC) 中的L1CAM ^{+细胞具有转移起始能力，并且我们定义了它们与组织再生的关系。}L1CAM 不在稳态肠上皮细胞中表达，但在结肠炎后的上皮再生和 CRC 类器官生长中被诱导和必需。通过使用人体组织和小鼠模型，我们表明 L1CAM 对于腺瘤的起始是可有可无的，但对于原位癌传播、肝转移定植和化学抗性是必需的。L1CAM^{高细胞与 LGR5高}细胞部分重叠人类 CRC 类器官中的干细胞样细胞。细胞间上皮接触的破坏导致 L1CAM 的 E-cadherin-REST 转录抑制，将化学抗性 CRC 祖细胞从 L1CAM^低状态转换为 L1CAM^高状态。因此，当上皮完整性丧失时，再生肠细胞中会出现 L1CAM 依赖性，这是一种部署在转移起始细胞中的伤口愈合表型。