集体细胞入侵(CCI),最具侵袭性的实体瘤,是癌细胞与其周围的细胞外基质(ECM)之间相互作用的新兴特性。然而,肿瘤群体总是由表达介导这种相互作用的粘附蛋白的可变水平的细胞组成,不允许直观地理解多细胞尺度的肿瘤侵袭性如何受到细胞-细胞和细胞-ECM粘附的空间异质性的影响。这里,我们使用了基于细胞Potts模型的多尺度计算框架,该框架是根据腺癌的组织病理学原理构建的。在早期对同质癌细胞群的研究中,这个框架揭示了相互作用的相对范围,包括驱动集体的细胞-细胞和细胞-ECM粘附,分散,和混合多式联运入侵。这里,我们构成了两个独立细胞亚群的肿瘤核心,这些细胞亚群显示了不同的细胞-细胞或细胞-ECM粘附强度。这两个细胞子集被排列为不同程度的空间混合,我们称之为异质性指数(HI)。我们观察到,低和高的亚群间细胞粘附有利于高HI和低HI混合群体的侵袭,具有不同的亚群内细胞-细胞粘附强度。分别。此外,对于细胞-ECM粘附强度的探索值,HI值高的人群总体上比HI值低的人群入侵得更好。然后我们询问如何通过逐渐混合的上皮细胞亚群来调节空间入侵,即,显示高细胞-细胞,但细胞-ECM粘附差,和间充质,即,与前者相反的粘合强度。这里也是,子集间粘连在说明HI和侵袭之间的比例关系中起着重要作用。对于异质细胞-ECM粘附的情况,可以看到这种关系的例外,其中具有较高ECM粘附力的细胞的外部定位较高的次最大HI模式比其相对较高的HI对应物更好地侵入。我们的模拟还揭示了粘附异质性如何证明集体入侵,当细胞-细胞或-ECM粘附类型变化时,但当两种粘附类型同时改变时,会导致侵入性分散。
Collective cell invasion (CCI), a canon of most invasive solid tumors, is an emergent property of the interactions between cancer cells and their surrounding extracellular matrix (ECM). However, tumor populations invariably consist of cells expressing variable levels of adhesive proteins that mediate such interactions, disallowing an intuitive understanding of how tumor invasiveness at a multicellular scale is influenced by spatial heterogeneity of cell-cell and cell-ECM adhesion. Here, we have used a Cellular Potts model-based multiscale computational framework that is constructed on the histopathological principles of glandular cancers. In earlier efforts on homogenous cancer cell populations, this framework revealed the relative ranges of interactions, including cell-cell and cell-ECM adhesion that drove collective, dispersed, and mixed multimodal invasion. Here, we constitute a tumor core of two separate cell subsets showing distinct intra- and inter-subset cell-cell or cell-ECM adhesion strengths. These two subsets of cells are arranged to varying extents of spatial intermingling, which we call the heterogeneity index (HI). We observe that low and high inter-subset cell adhesion favors invasion of high-HI and low-HI intermingled populations with distinct intra-subset cell-cell adhesion strengths, respectively. In addition, for explored values of cell-ECM adhesion strengths, populations with high HI values collectively invade better than those with lower HI values. We then asked how spatial invasion is regulated by progressively intermingled cellular subsets that are epithelial, i.e., showed high cell-cell but poor cell-ECM adhesion, and mesenchymal, i.e., with reversed adhesion strengths to the former. Here too, inter-subset adhesion plays an important role in contextualizing the proportionate relationship between HI and invasion. An exception to this relationship is seen for cases of heterogeneous cell-ECM adhesion where sub-maximal HI patterns with higher outer localization of cells with stronger ECM adhesion collectively invade better than their relatively higher-HI counterparts. Our simulations also reveal how adhesion heterogeneity qualifies collective invasion, when either cell-cell or cell-ECM adhesion type is varied but results in an invasive dispersion when both adhesion types are simultaneously altered.