Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States of America.
Department of Electrical and Computer Engineering, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States of America.
Biofabrication. 2021 Apr 7;13(3). doi: 10.1088/1758-5090/abe025.
tumor models consisting of cell spheroids are increasingly used for mechanistic studies and pharmacological testing. However, unless vascularized, the availability of nutrients such as glucose to deeper layers of multicellular aggregates is limited. In addition, recent developments in cells-only biofabrication (e.g. 'scaffold-free bioprinting'), allow the creation of more complex spheroid-based structures, further exposing the cells to nutrient deprivation within these constructs. To explore the impact of glucose availability on such tumor-like structures, we used the CompuCell3D platform for modeling of tumor spheroids. By monitoring the types of cells, fusing pairs geometry and the distance between spheroids centers of mass, we made novel heuristic observations on how binary- and multi-spheroid fusions are impacted by glucose availability. At limiting glucose concentrations mimicking hypoglycemia we noted an abrupt collapse of the tumor spheroids, unexpectedly amplified by the contact with normal cell spheroids. At higher glucose concentrations, we found an increased intermixing of cancerous cells, strong anti-phase oscillations between proliferating and quiescent tumor cells and a structural instability of fusing tumor spheroids, leading to their re-fragmentation. In a model of tumor microenvironment composed of normal cell spheroids fusing around a tumoral one, the competition for glucose lead to either the tumor's disappearance, to a steady state, or to its expansion. Moreover, the invasion of this microenvironment by individual tumor cells was also strongly depended on the available glucose. In conclusion, we demonstrate the value of computational simulations for anticipating the properties of biofabricated tumor models, and in generating testable hypotheses regarding the relationship between cancer, nutrition and diabetes.
肿瘤模型由细胞球组成，越来越多地用于机制研究和药物测试。然而，除非血管化，否则葡萄糖等营养物质在多细胞聚集体的深层的供应是有限的。此外，最近细胞仅生物制造的发展（例如“无支架生物打印”）允许创建更复杂的基于球体的结构，使细胞进一步暴露在这些结构内的营养剥夺中。为了探索葡萄糖供应对类似肿瘤结构的影响，我们使用 CompuCell3D 平台对肿瘤球体进行建模。通过监测细胞类型、融合对几何形状和球体质心之间的距离，我们对二聚体和多球体融合如何受到葡萄糖供应的影响提出了新的启发式观察。在模拟低血糖的有限葡萄糖浓度下，我们注意到肿瘤球体突然崩溃，与正常细胞球体的接触出乎意料地加剧了这种崩溃。在较高的葡萄糖浓度下，我们发现癌细胞之间的混合增加，增殖和静止肿瘤细胞之间的强反相振荡，以及融合肿瘤球体的结构不稳定，导致其重新碎片化。在由正常细胞球体融合围绕肿瘤球体组成的肿瘤微环境模型中，对葡萄糖的竞争导致肿瘤的消失、稳定状态或扩张。此外，单个肿瘤细胞对这种微环境的侵袭也强烈依赖于可用的葡萄糖。总之，我们证明了计算模拟在预测生物制造的肿瘤模型的性质以及生成有关癌症、营养和糖尿病之间关系的可测试假设方面的价值。
