Year: 2020
Type: article
Abstract: Cancer progression is driven by cell proliferation, apoptosis, and matrix invasion, which in turn depend on a myriad of factors including microenvironment stiffness, nutrient supply, and intercellular communication. Cell proliferation is regulated by volume, but in 3D clusters it remains unclear how multiple cells interact to control their size. 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 transporters, and the actomyosin cortex, that coordinate to manipulate cellular osmolarity. In connected cells, mechanical loading is shown to significantly affect how these components cooperate to transport ions, and precise volume control is impacted by the emergence of osmotic pressure gradients between cells. Consequent increases in cellular ion concentrations drive swelling, while a loss of ions impedes the compression resistance of cells. Combining the modeling framework with novel experiments, 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 provides new insight into the role of gap junctions in cancer progression and can help guide the development of therapeutics that target inter- and extra-cellular ion transport.
Source: Nature Communications
Authors: Eoin McEvoy, Yu Long Han, Ming Guo, Vivek B. Shenoy
Language: English
Topic: Connexins and lens biology
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,380
Awards: G1051554911, G155958390, Materials Research Science and Engineering Center, G2567800894, Epithelial layer jamming in breast cancer cell migration, G342638498, Liver Cancer: pre-Malignant Stiffening, Membrane Transduction, & Nuclear Rheology, G4212146726, Collaborative Research: Multiscale and Multiphasic Modeling of Single and Collective Migration in Fibrous Extracellular Matrices, G5558904534, G5743373210, G588188242, Integration of elasticity, viscosity, and plasticity in cellular mechanosensing, G643866923, G7125181322, G71947432, An integrated approach to melanoma metastasis and therapy resistance: effects of age-related changes in the ECM and the biomechanics of the skin, G7537657417, Quantitative analyses of tumor cell extravasation, Pathological consequences of altered tissue mechanics in fibrosis
OpenAlex ID: W3107308608