We determine how intercellular interactions and mechanical pressure experienced by single cells regulate cell proliferation using a minimal computational model for three-dimensional multicellular spheroid (MCS) growth. We discover that emergent spatial variations in the cell division rate, depending on the location of the cells either at the core or periphery within the MCS, is regulated by intercellular adhesion strength (fad). Varying fad results in nonmonotonic proliferation of cells in the MCS. A biomechanical feedback mechanism coupling the fad and microenvironment-dependent pressure fluctuations relative to a threshold value (pc) determines the onset of a dormant phase, and explains the nonmonotonic proliferation response. Increasing fad from low values enhances cell proliferation because pressure on individual cells is smaller compared with pc. However, at high fad, cells readily become dormant and cannot rearrange effectively in spacetime, leading to arrested cell proliferation. Utilizing our theoretical predictions, we explain experimental data on the impact of adhesion strength on cell proliferation and find good agreement. Our work, which shows that proliferation is regulated by pressure-adhesion feedback mechanism, may be a general feature of multicellular growth.
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