Intrinsic stochasticity in cell polarity and contact inhibition of locomotion

TL;DR

This study models how intrinsic molecular noise in cell polarity influences the variability of contact inhibition of locomotion (CIL) outcomes, revealing how protein copy number affects decision-making during cell collisions.

Contribution

It introduces a stochastic model simulating Rho GTPase dynamics to quantify noise effects on CIL variability based on contact properties and protein abundance.

Findings

Higher Rho GTPase copy number reduces polarity noise.

Weak or brief contacts are masked by molecular noise at low protein levels.

At high protein levels, CIL response variability reflects contact property variability.

Abstract

When cells collide, they often exhibit "contact inhibition of locomotion" (CIL), a behavior in which cells repolarize and migrate away from the site of contact. Experimental CIL outcomes are highly variable - why? Here, we develop a minimal stochastic model to quantify how intrinsic noise in cell polarity, arising from the finite number of signaling molecules, influences CIL decision-making. We simulate polarization dynamics by tracking individual Rho GTPase proteins that diffuse and switch stochastically between the cell membrane and cytosol. In the absence of cell-cell contact, the polarity axis diffuses rotationally - the cell's orientation wanders - with a diffusion coefficient that decreases as Rho GTPase copy number increases. Assuming that cell-cell contact inhibits Rho GTPase activation, we investigate how contact geometry, duration, and strength affect CIL sensitivity. At low protein copy number, weak, brief, or spatially narrow contacts are masked by molecular noise. In contrast, at high protein copy number, intrinsic polarity noise is negligible, and randomness in CIL response is more likely to reflect the variability from collision to collision in the cell-cell contact properties.