Zhang Tao, Ameen Shabeeb, Ghosh Sounok, Kim Kyungeun, Pandey Mrinal, Cheung Brian C H, Thanh Minh, Patteson Alison E, Wu Mingming, Schwarz J M
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China.
Department of Physics and BioInspired Institute, Syracuse, Syracuse University, Syracuse, NY 13244, United States of America.
New J Phys. 2025 Jul 1;27(7):073301. doi: 10.1088/1367-2630/ade81e. Epub 2025 Jul 10.
Embedding a collective of tumor cells, i.e. a tumor spheroid, in a fibrous environment, such as a collagen network, provides an essential platform to investigate the biophysical mechanisms of tumor invasion. To predict new mechanisms, we develop a three-dimensional computational model of an embedded spheroid using a vertex model, with cells represented as deformable polyhedrons, mechanically coupled to a fiber network via active linker springs. As the linker springs actively contract, the fiber network remodels. As we tune the rheology of the spheroid and the fiber network stiffness, we find that both factors affect the remodeling of the fiber network with fluid-like spheroids densifying and radially realigning the fiber network more on average than solid-like spheroids but only for a range of intermediate fiber network stiffnesses. Our predictions are supported by experimental studies comparing non-tumorigenic MCF10A spheroids and malignant MDA-MB-231 spheroids embedded in collagen networks. The spheroid rheology-dependent effects are the result of cellular motility generating spheroid shape fluctuations. These shape fluctuations lead to emergent feedback between the spheroid and the fiber network to further remodel the fiber network. This emergent feedback occurs only at intermediate fiber network stiffness since at low fiber network stiffness, the mechanical response of the coupled system is dominated by the spheroid and for high fiber network stiffness, the mechanical response is dominated by the fiber network. We are therefore able to quantify the regime of optimal spheroid-fiber network mechanical reciprocity. Our results uncover intricate morphological-mechanical interplay between an embedded spheroid and its surrounding fiber network with both spheroid contractile strength spheroid shape fluctuations playing important roles in the pre-invasion stages of tumor invasion.
将一群肿瘤细胞（即肿瘤球体）嵌入纤维环境（如胶原网络）中，为研究肿瘤侵袭的生物物理机制提供了一个重要平台。为了预测新机制，我们使用顶点模型开发了一个嵌入球体的三维计算模型，其中细胞表示为可变形多面体，通过活性连接弹簧与纤维网络机械耦合。随着连接弹簧的主动收缩，纤维网络会发生重塑。当我们调整球体的流变学特性和纤维网络的刚度时，我们发现这两个因素都会影响纤维网络的重塑，与固态球体相比，液态球体平均使纤维网络更致密且径向重新排列，但这仅在一定范围的中等纤维网络刚度下才会出现。我们的预测得到了实验研究的支持，这些实验比较了嵌入胶原网络中的非致瘤性MCF10A球体和恶性MDA - MB - 231球体。球体流变学相关效应是细胞运动性产生球体形状波动的结果。这些形状波动导致球体与纤维网络之间出现反馈，从而进一步重塑纤维网络。这种反馈仅在中等纤维网络刚度下出现，因为在低纤维网络刚度下，耦合系统的力学响应主要由球体主导，而在高纤维网络刚度下，力学响应主要由纤维网络主导。因此，我们能够量化球体 - 纤维网络最佳力学互易性的范围。我们的结果揭示了嵌入球体与其周围纤维网络之间复杂的形态 - 力学相互作用，球体收缩强度和球体形状波动在肿瘤侵袭的侵袭前阶段都起着重要作用。
