A Biophysical Model Uncovers the Size Distribution of Migrating Cell Clusters across Cancer Types
A Biophysical Model Uncovers the Size Distribution of Migrating Cell Clusters across Cancer Types
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DOI：
10.1158/0008-5472.can-19-1726
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发表时间：
2019-11-01
期刊：
影响因子：
11.2
通讯作者：
Onuchic, Jose Nelson
中科院分区：
文献类型：
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作者：
Bocci, Federico;Jolly, Mohit Kumar;Onuchic, Jose Nelson
从原发肿瘤的迁移是转移级联中的关键步骤。具有不同程度粘附和运动性的细胞迁移并作为单个循环肿瘤细胞（CTC）或多细胞CTC簇发射到血流中。最近测量了这些集群的频率和大小分布，但对这些不同迁移模式的潜在机制仍然知之甚少。我们提出了一个生物物理模型，耦合的上皮间质转化（EMT）和细胞迁移的表型可塑性，以解释个人和集体癌细胞迁移的模式。这种简化的物理模型捕获了细胞如何经历从个体迁移到集体细胞迁移的转变，并有力地概括了在几种癌症类型中实验观察到的CTC簇分数和尺寸分布，从而表明癌细胞迁移的潜在机制中存在共同特征。此外，我们确定的机制，可以最大限度地提高循环中的CTC簇的分数。首先，需要防止完全EMT并相反增加杂合上皮/间充质（E/M）细胞群体的机制来概括具有5至10个细胞的大簇的CTC尺寸分布。第二，多种中间E/M状态引起由具有不同上皮-间充质性状的细胞形成的较大且异质的簇。总体而言，该生物物理模型提供了一个平台，可以继续弥合癌细胞迁移的分子和生物物理调节之间的差距，并强调转移可能不需要完整的EMT。意义：癌细胞侵袭的生物物理模型整合了表型异质性和细胞迁移来解释循环肿瘤细胞簇的实验观察结果并提供新的预测。
Migration from the primary tumor is a crucial step in the metastatic cascade. Cells with various degrees of adhesion and motility migrate and are launched into the bloodstream as single circulating tumor cells (CTC) or multicellular CTC clusters. The frequency and size distributions of these clusters have been recently measured, but the underlying mechanisms enabling these different modes of migration remain poorly understood. We present a biophysical model that couples the phenotypic plasticity enabled by the epithelial-mesenchymal transition (EMT) and cell migration to explain the modes of individual and collective cancer cell migration. This reduced physical model captures how cells undergo a transition from individual migration to collective cell migration and robustly recapitulates CTC cluster fractions and size distributions observed experimentally across several cancer types, thus suggesting the existence of common features in the mechanisms underlying cancer cell migration. Furthermore, we identify mechanisms that can maximize the fraction of CTC clusters in circulation. First, mechanisms that prevent a complete EMT and instead increase the population of hybrid epithelial/mesenchymal (E/M) cells are required to recapitulate CTC size distributions with large clusters of 5 to 10 cells. Second, multiple intermediate E/M states give rise to larger and heterogeneous clusters formed by cells with different epithelial-mesenchymal traits. Overall, this biophysical model provides a platform to continue to bridge the gap between the molecular and biophysical regulation of cancer cell migration and highlights that a complete EMT might not be required for metastasis.Significance: A biophysical model of cancer cell invasion integrates phenotypic heterogeneity and cell migration to interpret experimental observations of circulating tumor cell clusters and provides new predictions.