Emergence of 3D stress-shape coupled chain-like cellular structures in embedded spheroids

The dynamics of tumor spheroids embedded in collagen networks, an important in vitro model for some cancers, are governed by cell-cell interactions and cell-collagen interactions. To determine how the interplay between the two sets of interactions can potentially lead to tumor cell breakout, we have constructed a three-dimensional computational model with the spheroid represented as a vertex model, the collagen network represented as a fiber network, and active springs coupling the two systems. With this model at a fixed fiber density, we have already found positive mechanical feedback between fluid spheroids and the fiber network that enhances both spheroid and fiber network remodeling [1]. Here, we vary the fiber density to find that at low fiber density, the spheroid morphology and mechanics is not influenced by the fiber network. However, at higher fiber density, the fiber network is effectively able to fluidize an initially solid spheroid such that the spheroid morphology and mechanics is influenced by the fiber network. To further understand this phenomenon, we develop an analytical expression for the 3D vertex model cell stress. We observe chain-like high stress-shape coupled structures spanning the embedded tumor in fluid spheroids, rather than in solid spheroids. High fiber density promotes these structures by enhancing spheroid fluidity. These structures may facilitate cells breaking out of the spheroid. However, the alignment of fibers via force-mediated physical remodeling is also more difficult in such an environment. These competitive influences suggest a critical level of connectivity for ECM that maximizes the potential for tumor metastasis.

[1] Tao Zhang, Shabeeb Ameen, Sounok Ghosh, Kyungeun Kim, Minh Thanh, Alison E. Patteson, Mingming Wu, J. M. Schwarz, Enhanced extracellular matrix remodeling due to embedded spheroid fluidization, arXiv:2403.16784