A simple framework for agent-based modeling with extracellular matrix

Abstract

Extracellular matrix (ECM) is a key part of the cellular microenvironment and critical in multiple disease and developmental processes. Representing ECM and cell–ECM interactions is a challenging multi–scale problem that acts across the tissue and cell scales. While several computational frameworks exist for ECM modeling, they typically focus on very detailed modeling of individual ECM fibers or represent only a single aspect of the ECM. Using the PhysiCell agent–based modeling platform, we combine aspects of previous modeling efforts and develop a framework of intermediate detail that addresses direct cell–ECM interactions. We represent a small region of ECM as an ECM element containing 3 variables: anisotropy, density, and orientation. We then place many ECM elements through a space to form an ECM. Cells have a mechanical response to the local ECM variables and remodel ECM based on their velocity. We demonstrate aspects of this framework with a model of cell invasion where the cell's motile phenotype is driven by the ECM microstructure patterned by prior cells' movements. Investigating the limit of high–speed communication and with stepwise introduction of the framework features, we generate a range of cellular dynamics and ECM patterns — from recapitulating a homeostatic tissue, to indirect communication of paths (stigmergy), to collective migration. When we relax the high–speed communication assumption, we find that the behaviors persist but can be lost as rate of signal generation declines. This result suggests that cell–cell communication mitigated via the ECM can constitute an important mechanism for pattern formation in dynamic cellular patterning while other processes likely also contribute to leader-follower behavior.

Drug-loaded nanoparticles for cancer therapy: a high-throughput multicellular agent-based modeling study

“…See [33] for full algorithmic detail, numerical testing, and a variety of examples. PhysiCell has been applied to a broad variety of multicellular system problems, such as oncolytic virus therapy, cancer immunology, tissue mechanics, infection dynamics and tissue damage, cancer mRNA vaccine treatments, cancer cell migration, extracellular matrix remodeling, and cellular fusion, among others [36, 37, 38, 39, 40, 41, 42, 43, 44]. See [32] for detailed review of cell-based computational modeling in cancer biology.…”

“…PhysiCell has been applied to a broad variety of multicellular system problems, such as oncolytic virus therapy, cancer immunology, tissue mechanics, infection dynamics and tissue damage, cancer mRNA vaccine treatments, cancer cell migration, extracellular matrix remodeling, and cellular fusion, among others [36,37,38,39,40,41,42,43,44].…”

PhysiMeSS - A New PhysiCell Addon for Extracellular Matrix Modelling

“…The open-source computational package PhysiCell [7], which implements a multiscale hybrid ABM (having both agent and continuum aspects) has hitherto been used to describe such processes as the invasion of cancer cells [12, 15], cancer-immune responses [9], and most recently the progression and spread of COVID-19 within the human body [6]. The underlying environment in which these cellular dynamics take place is typically modelled, in PhysiCell, as a distribution of some substrate of interest.…”

“…Often this influence is to cause cells to undergo some form of taxis, whereby the motility of cells is directed along the gradients of the substrate. Both haptotaxis (movement of cells up cellular-adhesion site gradients) [14] and durotaxis (movement of cells up gradients of matrix stiffness) [12] have been modelled in this way. Whilst such an approach is useful, it does not allow for fine-grained modelling of the specific extracellular matrix (ECM) components which also, importantly, interact mechanically with cellular agents.…”