Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Cancer. 2020 Jan;1(1):28-45. doi: 10.1038/s43018-019-0006-x. Epub 2020 Jan 13.
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 cells partially overlap with LGR5 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 to an L1CAM 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性，但它们的起源及其与原发性肿瘤起始干细胞的关系尚不清楚。我们表明，人结直肠癌（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 不在稳态肠道上皮中表达，但在结肠炎后上皮再生和 CRC 类器官生长中被诱导和需要。通过使用人类组织和小鼠模型，我们表明 L1CAM 对于腺瘤起始不是必需的，但对于原位癌的传播、肝转移定植和化学抗性是必需的。L1CAM 细胞在人 CRC 类器官中与 LGR5 干细胞样细胞部分重叠。细胞间上皮接触的破坏导致 E-钙粘蛋白-REST 转录对 L1CAM 的去抑制，将化学抗性 CRC 祖细胞从 L1CAM 状态切换到 L1CAM 状态。因此，当上皮完整性丧失时，L1CAM 依赖性出现在再生肠道细胞中，这是转移起始细胞中用于伤口愈合的表型。
