RT Journal Article
SR Electronic
T1 Dual Role of Cell-Cell Adhesion In Tumor Suppression and Proliferation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 683250
DO 10.1101/683250
A1 Abdul N Malmi-Kakkada
A1 Xin Li
A1 Sumit Sinha
A1 D. Thirumalai
YR 2019
UL http://biorxiv.org/content/early/2019/07/11/683250.abstract
AB 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 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 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.