Self-organization in brain tumors: how cell morphology and cell density influence glioma pattern formation

Abstract

AbstractModeling cancer cells is essential to better understand the dynamic nature of brain tumors and glioma cells, including their invasion of normal brain. Our goal is to study how the morphology of the glioma cell influences the formation of patterns of collective behavior such as flocks (cells moving in the same direction) or streams (cells moving in opposite direction) referred to as oncostream. We have observed experimentally that the presence of oncostreams correlates with tumor progression. We propose an original agent-based model that considers each cell as an ellipsoid. We show that stretching cells from round to ellipsoid increases stream formation.A systematic numerical investigation of the model was implemented in ℝ2. We deduce a phase diagram identifying key regimes for the dynamics (e.g. formation of flocks, streams, scattering). Moreover, we study the effect of cellular density and show that, in contrast to classical models of flocking, increasing cellular density reduces the formation of flocks. We observe similar patterns in ℝ3 with the noticeable difference that stream formation is more ubiquitous compared to flock formation.Author summarySelf-organization is the formation of large-scale multicellular patterns that result exclusively from the interactions amongst constituent single cells. To establish the existence of self-organization in brain tumors we used agent-based modeling based on data extracted from static and dynamic genetically engineered mouse glioma models. Implementation of our model in ℝ2 identifies the dynamics that lead to formation of flocks (cells moving in a single direction), streams (cells moving in two directions), and cells moving as swarms or scattering. Increasing cellular density reduced formation of flocks and increased the formation of streams both in ℝ2 and in ℝ3. These results demonstrate the detailed mechanism leading to self-organization in brain tumors. As increasing density of oncostreams correlates with tumor malignancy, we establish a pathophysiological link between self-organization of glioma tumors and glioma malignancy. We propose the dismantling of oncostreams as a new therapeutic approach to the treatment of brain tumors.