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

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 local spatial patterns of cell growth 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.

Interparticle Adhesion Regulates the Surface Roughness of Growing Dense Three-Dimensional Active Particle Aggregates

“…We briefly describe the simulation scheme adapted from our previous works on 3D tumor growth. − In the present study, we perform an off-lattice simulation of a growing 3D dense active particle aggregate. , In the growing aggregate (see Supporting Information, Movies 1–3), individual particles are modeled as soft spherical agents, which grow stochastically in time and undergo division into daughter agents on reaching a critical size. The physics of the aggregate growth is governed by two factors: (a) systematic mechanical forces arising from two body interactions and (b) active processes due to particle growth, division and death, as we explain further below.…”

“…In the KPZ model, the particle flux is orthogonal to the growing interface whereas another interesting scenario deals with particle flux generated by the surface itself as is relevant in biological systems such as membranes and cell collectives. − In this context, Risler et al described the out-of-equilibrium surface fluctuations of cell collectives in the homeostatic state when cell birth and death are balanced. Building on our prior work − where we modeled biological cells with pairwise elastic and adhesive interaction in addition to rules for size growth, division, and death of particles, we study the surface roughness of a dense and fast expanding three-dimensional (3D) collection of active particles. We focus on investigating 3D aggregate boundary expansion at varying interparticle adhesion strengths, known to critically tune collective properties of active matter systems.…”

Self-generated persistent random forces drive phase separation in growing tumors

“…We performed t-SNE on data generated using simulations of an expanding tumor spheroid model 15,18,29,30 . The results revealed massive dynamical heterogeneity that depends on the radial distance from the tumor center, which accords well with the conclusions in recent experiments [11][12][13] .…”