An Integrative and Modular Framework to Recapitulate Emergent Behavior in Cell Migration

Marina B Cuenca,Carolina Perez-Castro,Hernan E Grecco,Lucía Canedo

doi:10.3389/fcell.2020.615759

Abstract

Cell migration has been a subject of study in a broad variety of biological systems, from morphogenetic events during development to cancer progression. In this work, we describe single-cell movement in a modular framework from which we simulate the collective behavior of glioblastoma cells, the most prevalent and malignant primary brain tumor. We used the U87 cell line, which can be grown as a monolayer or spatially closely packed and organized in 3D structures called spheroids. Our integrative model considers the most relevant mechanisms involved in cell migration: chemotaxis of attractant factor, mechanical interactions and random movement. The effect of each mechanism is integrated into the overall probability of the cells to move in a particular direction, in an automaton-like approach. Our simulations fit and reproduced the emergent behavior of the spheroids in a set of migration assays where single-cell trajectories were tracked. We also predicted the effect of migration inhibition on the colonies from simple experimental characterization of single treated cell tracks. The development of tools that allow complementing molecular knowledge in migratory cell behavior is relevant for understanding essential cellular processes, both physiological (such as organ formation, tissue regeneration among others) and pathological perspectives. Overall, this is a versatile tool that has been proven to predict individual and collective behavior in U87 cells, but that can be applied to a broad variety of scenarios.

Highlights

Collective cell motion is a complex feature in biological systems, crucial for morphogenetic events, where many single-cell level processes are involved
Other cells did not show protrusions but migrated in pairs, which reinforced the existence of mechanical interactions (Figure 1C, Supplementary Video 3)
From a simple determination of the cell diffusion coefficient, our model can replicate a set of migration assays of U87 cellular spheroids

Summary

Introduction

Collective cell motion is a complex feature in biological systems, crucial for morphogenetic events, where many single-cell level processes are involved. Chemotaxis, mechanical interactions (with other cells and extracellular matrix) and proliferation have been identified as key mechanisms driving cell migration (Kansal et al, 2000; Khain et al, 2005; Rubenstein and Kaufman, 2008; Charteris and Khain, 2014; Li et al, 2017; Manini et al, 2018) How these processes individually contribute to the emergent behavior is not fully understood as we are limited to either observing single cells or the collective behavior at the multicellular level. In cellular automaton discrete models cells move according to specific rules or probabilities that depend on the neighboring distribution This approach would allow us to describe the social behavior within cell communities at the singlecell level. To the best of our knowledge, there are no existing models that integrate the broad diversity of biological mechanisms needed to fully predict cell migration

Methods

Results

Conclusion