Burger Gerhard A, van de Water Bob, Le Dévédec Sylvia E, Beltman Joost B
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands.
Front Cell Dev Biol. 2022 Apr 25;10:854721. doi: 10.3389/fcell.2022.854721. eCollection 2022.
The ability of cancer cells to invade neighboring tissue from primary tumors is an important determinant of metastatic behavior. Quantification of cell migration characteristics such as migration speed and persistence helps to understand the requirements for such invasiveness. One factor that may influence invasion is how local tumor cell density shapes cell migration characteristics, which we here investigate with a combined experimental and computational modeling approach. First, we generated and analyzed time-lapse imaging data on two aggressive Triple-Negative Breast Cancer (TNBC) cell lines, HCC38 and Hs578T, during 2D migration assays at various cell densities. HCC38 cells exhibited a counter-intuitive increase in speed and persistence with increasing density, whereas Hs578T did not exhibit such an increase. Moreover, HCC38 cells exhibited strong cluster formation with active pseudopod-driven migration, especially at low densities, whereas Hs578T cells maintained a dispersed positioning. In order to obtain a mechanistic understanding of the density-dependent cell migration characteristics and cluster formation, we developed realistic spatial simulations using a Cellular Potts Model (CPM) with an explicit description of pseudopod dynamics. Model analysis demonstrated that pseudopods exerting a pulling force on the cell and interacting increased adhesion at pseudopod tips could explain the experimentally observed increase in speed and persistence with increasing density in HCC38 cells. Thus, the density-dependent migratory behavior could be an emergent property of single-cell characteristics without the need for additional mechanisms. This implies that pseudopod dynamics and interaction may play a role in the aggressive nature of cancers through mediating dispersal.
癌细胞从原发性肿瘤侵袭邻近组织的能力是转移行为的一个重要决定因素。对细胞迁移特征（如迁移速度和持续性）进行量化有助于理解这种侵袭性的必要条件。一个可能影响侵袭的因素是局部肿瘤细胞密度如何塑造细胞迁移特征，我们在此采用实验与计算建模相结合的方法对此进行研究。首先，我们在不同细胞密度的二维迁移实验中，生成并分析了两种侵袭性三阴性乳腺癌（TNBC）细胞系HCC38和Hs578T的延时成像数据。HCC38细胞随着密度增加，速度和持续性出现了与直觉相反的增加，而Hs578T细胞则未表现出这种增加。此外，HCC38细胞表现出强烈的簇集形成，伴有活跃的伪足驱动迁移，尤其是在低密度时，而Hs578T细胞保持分散定位。为了从机制上理解密度依赖性细胞迁移特征和簇集形成，我们使用细胞Potts模型（CPM）开发了逼真的空间模拟，明确描述了伪足动力学。模型分析表明，伪足对细胞施加拉力并在伪足尖端增加粘附相互作用，可以解释在HCC38细胞中实验观察到的随着密度增加速度和持续性的增加。因此，密度依赖性迁移行为可能是单细胞特征的一种涌现特性，无需额外的机制。这意味着伪足动力学和相互作用可能通过介导扩散在癌症的侵袭性中发挥作用。
