Intercellular adhesion mediates non-monotonic growth of cell collectives due to biomechanical feedback

The growth of cell collectives is governed by the interplay of many physical and biological factors, ranging from intercellular forces to gene expression in individual cells. Even though biomechanical forces arise due to the growth and division of individual cells, little is known about this fundamental aspect of collective cell growth. By implementing a minimal computational model for three-dimensional multicellular spheroids (MCS), we determine how intercellular adhesive interactions and mechanical pressure on single cells regulate cell division. We discover that emergent spatial variations in the cell division rate, with cells at the periphery of the MCS dividing rapidly while cells at the core undergo little to no division, are regulated by intercellular adhesion strength. Varying cell-cell adhesion strength results in non-monotonic MCS growth. A biomechanical feedback mechanism coupling intercellular adhesion strength and microenvironment-dependent pressure experienced by cells determines the onset of a dormant phase, and explains the non-monotonic proliferation response. Our work, which shows that proliferation is regulated by a pressure-adhesion feedback mechanism, maybe a general feature of multicellular growth.