Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, Manassas, VA, 20110, USA.
Sci Rep. 2019 Nov 22;9(1):17380. doi: 10.1038/s41598-019-53850-7.
Tumor clonal heterogeneity drives treatment resistance. But robust models are lacking that permit eavesdropping on the basic interaction network of tumor clones. We developed an in vitro, functional model of clonal cooperation using U87MG glioblastoma cells, which isolates fundamental clonal interactions. In this model pre-labeled clones are co-cultured to track changes in their individual motility, growth, and drug resistance behavior while mixed. This highly reproducible system allowed us to address a new class of fundamental questions about clonal interactions. We demonstrate that (i) a single clone can switch off the motility of the entire multiclonal U87MG cell line in 3D culture, (ii) maintenance of clonal heterogeneity is an intrinsic and influential cancer cell property, where clones coordinate growth rates to protect slow growing clones, and (iii) two drug sensitive clones can develop resistance de novo when cooperating. Furthermore, clonal communication for these specific types of interaction did not require diffusible factors, but appears to depend on cell-cell contact. This model constitutes a straightforward but highly reliable tool for isolating the complex clonal interactions that make up the fundamental "hive mind" of the tumor. It uniquely exposes clonal interactions for future pharmacological and biochemical studies.
肿瘤克隆异质性导致治疗耐药。但是，缺乏强大的模型来监测肿瘤克隆的基本相互作用网络。我们使用 U87MG 神经胶质瘤细胞开发了一种体外功能克隆合作模型，该模型可分离基本的克隆相互作用。在这种模型中，预先标记的克隆被共培养，以跟踪它们在混合时的个体迁移率、生长和耐药性行为的变化。这种高度可重复的系统使我们能够解决关于克隆相互作用的一类新的基本问题。我们证明了 (i) 单个克隆可以在 3D 培养中关闭整个多克隆 U87MG 细胞系的迁移能力，(ii) 克隆异质性的维持是一种内在的、有影响力的癌细胞特性，其中克隆协调生长速度以保护生长缓慢的克隆，以及 (iii) 当合作时，两个药物敏感的克隆可以从头开始发展耐药性。此外，这些特定类型相互作用的克隆通讯不需要可扩散因子，而是似乎依赖于细胞-细胞接触。该模型构成了一种简单但非常可靠的工具，可用于分离构成肿瘤基本“蜂巢思维”的复杂克隆相互作用。它为未来的药理学和生化研究独特地揭示了克隆相互作用。
