Abstract
Studies on pattern formation in coculture cell systems can provide insights into many physiological and pathological processes. Here, we investigate how the extracellular matrix (ECM) may influence the patterning in coculture systems. The model coculture system we use is composed of highly motile invasive breast cancer cells, initially mixed with inert nonmetastatic cells on a 2D substrate and covered with a Matrigel layer introduced to mimic ECM. We observe that the invasive cells exhibit persistent centripetal motion and yield abnormal aggregation, rather than random spreading, due to a “collective pulling” effect resulting from ECM-mediated transmission of active contractile forces generated by the polarized migration of the invasive cells along the vertical direction. The mechanism we report may open a new window for the understanding of biological processes that involve multiple types of cells.
Highlights
Phenotypic and functional heterogeneities arise among cells during development and differentiation, as a consequence of gene expression and environmental changes in a multicellular organism [1]
We have built a coculture system containing a mixture of two different types of cells, i.e., highly invasive breast cancer cells (MDA-MB-231) and nonmetastatic cells (MCF-7) on a 2D substrate, which are covered with a layer of 100% Matrigel
To further investigate the effects of the cell-extracellular matrix (ECM) mechanical coupling on collectively polarized invading cells, we develop a novel active-particle-on-network model, which explicitly considers the mechanical coupling between distant cells through ECM network-mediated active force propagation [19, 21,22,23, 29, 30], rather than imposing a simplified effective interaction between nearby cells [31, 32]
Summary
Phenotypic and functional heterogeneities arise among cells during development and differentiation, as a consequence of gene expression and environmental changes in a multicellular organism [1]. In studies on coculture systems used to investigate embryogenesis, wound healing, and tissue engineering [13,14,15], widely implicated is the so-called differentialadhesion hypothesis (DAH), which assumes that a multicellular system can be treated as a Newtonian fluid system. In such a system, when two types of liquids with different surface tensions are mixed together, the final state is given by the requirement that the system has a minimum surface free energy; viz., the two types of liquids would separate, with the Research type of stronger adhesion staying in the center and that of weaker adhesion staying outside. Pawlizak et al found that DAH was not enough to interpret their experimental observation and suggested that cell mobility should be included as an additional parameter [16]
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