Dual Role of Cell-Cell Adhesion In Tumor Suppression and Proliferation Due to Collective Mechanosensing

TL;DR

This study reveals that cell-cell adhesion has a dual role in tumor growth, where increasing adhesion initially promotes proliferation by reducing intercellular pressure, but excessive adhesion inhibits growth, highlighting a non-monotonic relationship.

Contribution

The paper introduces a theoretical model demonstrating a non-monotonic influence of cell-cell adhesion on proliferation, supported by experimental data, and elucidates a feedback mechanism involving pressure and adhesion.

Findings

Proliferation peaks at an optimal adhesion level.

Intercellular pressure decreases with increasing adhesion up to a point.

Experimental results align with the model's predictions.

Abstract

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.