Adhesion strength between cells regulate non-monotonic growth by a biomechanical feedback mechanism

We probe the interplay between intercellular interactions and pressure fluctuations associated with single cells in regulating cell proliferation using simulations of a minimal model for three-dimensional multicellular spheroid (MCS) growth. The emergent spatial variations in the cell division rate, that depends on the location of the cells within the MCS, is regulated by intercellular adhesion strength ( f ad ). This in turn results in non-monotonic proliferation of cells in the MCS with varying adhesion strength, which accords well with experimental results. A biomechanical feedback mechanism coupling the f ad and cell-dependent pressure fluctuations relative to a threshold value ( p c ) determines the onset of a dormant phase, and explains the non-monotonic proliferation response. Increasing f ad from low values enhances cell proliferation because pressure on individual cells is smaller compared to p c . In contrast, at high f ad , cells readily become dormant and cannot rearrange effectively, leading to arrested cell proliferation. Our work, which shows that proliferation is regulated by pressure-adhesion feedback loop, may be a general feature of tumor growth.