Department of Biomedical Engineering, Wake Forest School of Medicine, 575 N. Patterson Ave., Suite 530, Winston-Salem, NC, 27101, USA.
Virginia Tech - Wake Forest University School of Biomedical Engineering and Sciences, Blacksburg, VA, USA.
Sci Rep. 2020 Jul 14;10(1):11583. doi: 10.1038/s41598-020-68324-4.
Multicellular tumor spheroid (MCTS) systems provide an in vitro cell culture model system which mimics many of the complexities of an in vivo solid tumor and tumor microenvironment, and are often used to study cancer cell growth and drug efficacy. Here, we present a coupled experimental-computational framework to estimate phenotypic growth and biophysical tumor microenvironment properties. This novel framework utilizes standard microscopy imaging of MCTS systems to drive a biophysical mathematical model of MCTS growth and mechanical interactions. By extending our previous in vivo mechanically-coupled reaction-diffusion modeling framework we developed a microscopy image processing framework capable of mechanistic characterization of MCTS systems. Using MDA-MB-231 breast cancer MCTS, we estimated biophysical parameters of cellular diffusion, rate of cellular proliferation, and cellular tractions forces. We found significant differences in these model-based biophysical parameters throughout the treatment time course between untreated and treated MCTS systems, whereas traditional size-based morphometric parameters were inconclusive. The proposed experimental-computational framework estimates mechanistic MCTS growth and invasion parameters with significant potential to assist in better and more precise assessment of in vitro drug efficacy through the development of computational analysis methodologies for three-dimensional cell culture systems to improve the development and evaluation of antineoplastic drugs.
多细胞肿瘤球体 (MCTS) 系统提供了一种体外细胞培养模型系统，可模拟体内实体瘤和肿瘤微环境的许多复杂性，常用于研究癌细胞生长和药物疗效。在这里，我们提出了一种结合实验和计算的框架来估计表型生长和生物物理肿瘤微环境特性。这个新颖的框架利用 MCTS 系统的标准显微镜成像来驱动 MCTS 生长和机械相互作用的生物物理数学模型。通过扩展我们之前开发的用于体内机械耦合反应扩散建模的框架，我们开发了一种显微镜图像处理框架，能够对 MCTS 系统进行机械特征化。使用 MDA-MB-231 乳腺癌 MCTS，我们估计了细胞扩散、细胞增殖速度和细胞牵引力的生物物理参数。我们发现，在未处理和处理的 MCTS 系统之间的整个治疗过程中，这些基于模型的生物物理参数存在显著差异，而传统的基于大小的形态计量参数则没有定论。所提出的实验计算框架估计了 MCTS 生长和入侵的机械参数，具有很大的潜力通过开发用于三维细胞培养系统的计算分析方法来协助更好和更精确地评估体外药物疗效，从而改进抗肿瘤药物的开发和评估。
