  It is known that mechanical interactions couple a cell to its neighbors,
enabling a feedback loop to regulate tissue growth. However, the interplay
between cell-cell adhesion strength, local cell density and force fluctuations
in regulating cell proliferation is poorly understood. Here, we show that
spatial variations in the tumor growth rates, which depend on the location of
cells within tissue spheroids, are strongly influenced by cell-cell adhesion.
As the strength of the cell-cell adhesion increases, intercellular pressure
initially decreases, enabling dormant cells to more readily enter into a
proliferative state. We identify an optimal cell-cell adhesion regime where
pressure on a cell is a minimum, allowing for maximum proliferation. We use a
theoretical model to validate this novel collective feedback mechanism coupling
adhesion strength, local stress fluctuations and proliferation.Our results,
predicting the existence of a non-monotonic proliferation behavior as a
function of adhesion strength, are consistent with experimental results.
Several experimental implications of the proposed role of cell-cell adhesion in
proliferation are quantified, making our model predictions amenable to further
experimental scrutiny. We show that the mechanism of contact inhibition of
proliferation, based on a pressure-adhesion feedback loop, serves as a unifying
mechanism to understand the role of cell-cell adhesion in proliferation.
