Mathematical modeling of leader-follower cell invasion of tumor-associated stroma using a novel extracellular matrix model

Collective cell migration and invasion are challenging topics to study as diverse biological processes may drive these behaviors. Mathematical modeling informed by biological experiments can lead to new insights. Here, we focus on a particular form of collective migration: collective invasion of tumor-associated stroma via a cell-based leader-follower mechanism. For the stroma, we implement a novel, simple extracellular matrix (ECM) model using three variables to represent a unit of ECM: a fiber density, anisotropy, and orientation. Furthermore, we implement bi-directional interactions between cells, represented as discrete agents, and the ECM. Cells remodel the ECM within their vicinity based on their motion and the ECM alters cellular motility. With this representation, we attempt to recapitulate experimental results of an organoid model of invasive breast cancer through a series of models that build additively on one another to introduce new biological hypotheses as additional agent model rules. Despite the increasing complexity of individual cells and short-range interactions, we find that our results do not significantly vary from one model to the next in overall qualitative behavior. This suggests that long range ECM remodeling and asymmetric cell-cell attachment/detachment processes might be necessary to recapitulate experimental results. By proxy, it also suggests that these phenomena may possibly be necessary to enable collective invasion of ECM in organoid systems.