Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA.
Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, USA.
Nat Commun. 2020 Dec 1;11(1):6148. doi: 10.1038/s41467-020-19904-5.
Sustained proliferation is a significant driver of cancer progression. Cell-cycle advancement is coupled with cell size, but it remains unclear how multiple cells interact to control their volume in 3D clusters. In this study, we propose a mechano-osmotic model to investigate the evolution of volume dynamics within multicellular systems. Volume control depends on an interplay between multiple cellular constituents, including gap junctions, mechanosensitive ion channels, energy-consuming ion pumps, and the actomyosin cortex, that coordinate to manipulate cellular osmolarity. In connected cells, we show that mechanical loading leads to the emergence of osmotic pressure gradients between cells with consequent increases in cellular ion concentrations driving swelling. We identify how gap junctions can amplify spatial variations in cell volume within multicellular spheroids and, further, describe how the process depends on proliferation-induced solid stress. Our model may provide new insight into the role of gap junctions in breast cancer progression.
持续增殖是癌症进展的重要驱动因素。细胞周期的推进伴随着细胞大小的增加，但多个细胞如何相互作用以控制其在 3D 簇中的体积仍不清楚。在这项研究中，我们提出了一个机械渗透模型来研究多细胞系统中体积动力学的演变。体积控制取决于多种细胞成分之间的相互作用，包括间隙连接、机械敏感离子通道、耗能离子泵和肌动球蛋白皮质，它们协同作用以调节细胞渗透压。在连接的细胞中，我们表明机械加载会导致细胞之间出现渗透压梯度，从而导致细胞内离子浓度增加，导致细胞肿胀。我们确定了间隙连接如何在多细胞球体中放大细胞体积的空间变化，并且进一步描述了该过程如何取决于增殖诱导的固体应力。我们的模型可以为间隙连接在乳腺癌进展中的作用提供新的见解。
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