Colorectal cancer (CRC) tumors are composed of heterogeneous and plastic cell populations, including a pool of cancer stem cells that express LGR5. Whether these distinct cell populations display different mechanical properties, and how these properties might contribute to metastasis is poorly understood. Using CRC patient derived organoids (PDOs), we find that compared to LGR5- cells, LGR5+ cancer stem cells are stiffer, adhere better to the extracellular matrix (ECM), move slower both as single cells and clusters, display higher nuclear YAP, show a higher survival rate in response to mechanical confinement, and form larger transendothelial gaps. These differences are largely explained by the downregulation of the membrane to cortex attachment proteins Ezrin/Radixin/Moesin (ERMs) in the LGR5+ cells. By analyzing single cell RNA-sequencing (scRNA-seq) expression patterns from a patient cohort, we show that this downregulation is a robust signature of colorectal tumors. Our results show that LGR5- cells display a mechanically dynamic phenotype suitable for dissemination from the primary tumor whereas LGR5+ cells display a mechanically stable and resilient phenotype suitable for extravasation and metastatic growth.

结直肠癌 (CRC) 肿瘤由异质性和可塑性细胞群组成，其中包括表达 LGR5 的癌症干细胞库。这些不同的细胞群是否表现出不同的机械特性，以及这些特性如何促进转移，人们知之甚少。使用 CRC 患者来源的类器官 (PDO)，我们发现与 LGR5- 细胞相比，LGR5+ 癌症干细胞更坚硬，更好地粘附到细胞外基质 (ECM)，作为单细胞和细胞簇移动更慢，显示更高的核 YAP，显示对机械限制的反应更高的存活率，并形成更大的跨内皮间隙。这些差异很大程度上是由于 LGR5+ 细胞中膜与皮质附着蛋白 Ezrin/Radixin/Moesin (ERM) 的下调所致。通过分析患者队列的单细胞 RNA 测序 (scRNA-seq) 表达模式，我们发现这种下调是结直肠肿瘤的一个强有力的特征。我们的结果表明，LGR5-细胞表现出适合从原发肿瘤传播的机械动态表型，而LGR5+细胞表现出适合外渗和转移生长的机械稳定和弹性表型。