PhysiCell: an Open Source Physics-Based Cell Simulator for 3-D Multicellular Systems

Abstract

Many multicellular systems problems can only be understood by studying how cells move, grow, divide, interact, and die. Tissue-scale dynamics emerge from systems of many interacting cells as they respond to and influence their microenvironment. The ideal "virtual laboratory" for such multicellular systems simulates both the biochemical microenvironment (the "stage") and many mechanically and biochemically interacting cells (the "players" upon the stage).PhysiCell-physics-based multicellular simulator-is an open source agent-based simulator that provides both the stage and the players for studying many interacting cells in dynamic tissue microenvironments. It builds upon a multi-substrate biotransport solver to link cell phenotype to multiple diffusing substrates and signaling factors. It includes biologically-driven sub-models for cell cycling, apoptosis, necrosis, solid and fluid volume changes, mechanics, and motility "out of the box." The C++ code has minimal dependencies, making it simple to maintain across platforms. PhysiCell has been parallelized with OpenMP, and its performance scales linearly with the number of cells. Simulations up to 10 5 -10 6 cells are feasible on quad-core desktop workstations; larger simulations are attainable on single HPC compute nodes.We demonstrate PhysiCell by simulating the impact of necrotic core biomechanics, 3-D geometry, and stochasticity on the dynamics of hanging drop tumor spheroids and ductal carcinoma in situ (DCIS) of the breast. We also demonstrate stochastic motility, chemical and contact-based interaction of multiple cell types, and the extensibility of PhysiCell with examples in synthetic multicellular systems (a "cellular cargo delivery" system, with application to anti-cancer treatments), cancer heterogeneity, and cancer immunology. PhysiCell is a powerful multicellular systems simulator that will be continually improved with new sub-models, capabilities, and performance improvements. It also represents a significant independent code base for replicating results from other simulation platforms. The PhysiCell source code, examples, documentation, and support are available under the BSD license at http://PhysiCell.MathCancer.org and http://PhysiCell.sf.net. This paper introducesPhysiCell: an open source, agent-based model for 3-D multicellular simulations. It includes a standard library of sub-models for cell fluid and solid volume changes, cycle progression, apoptosis, necrosis, mechanics, and motility. PhysiCell is directly coupled to a biotransport solver to simulate many diffusing substrates and cell-secreted signals. Each cell can dynamically update its phenotype based on its microenvironmental conditions. Users can customize or replace the included sub-models.PhysiCell runs on a variety of platforms (Linux, OSX, and Windows) with few software dependencies. Its computational cost scales linearly in the number of cells. It is feasible to simulate 500,000 cells on quad-core desktop workstations, and millions of cells on single HPC compute nodes. We demonstrat...

PhysiBoSS: a multi-scale agent based modelling framework integrating physical dimension and cell signalling

“…To address the issue of including individual cell description into an agent-based model, we adapted, merged and expanded two existing open source software. The first, PhysiCell [38], focuses on the evolution of a tumour by simulating the dynamics of a population of cells under specific constraints, in 2D or in 3D. The second one, MaBoSS [36,37], defines a contiuous-time Markov process on the state transition graph of a Boolean model and allows the quantification of probability of visiting some selected model states.…”

“…Thus, cell-centred, off-lattice models seemed an appropriate choice of agent-based models to be used [9,39,40]. Among the available tools implementing cell-centred agent-based models, CellSys [15], Chaste [41] and PhysiCell [38,42] were particularly interesting.…”

“…We used PhysiCell source code as a basis for our agent-based model part of our software because of its open-sourced development and its overall simplicity. PhysiCell is a freely available, open-source C++ software (physicell.mathcancer.org, [38]). Cells are approximated as spheres which allows for cheaper computation and simpler description than more realistic frameworks.…”

“…• PhysiCell core, that handles the representation of the cells' mechanics [38] and key phenotypic behaviors. A cell is represented as a sphere with two radii, cellular and nuclear.…”

“…To explore the whole cell population dynamics, the cellular signalling mechanisms and the interplay between cells and their surrounding (i.e., other cells or the microenvironment), we propose to combine an agent-based approach with a Boolean representation of biochemical events taking place in each cell. For that purpose, we have developed a new software, PhysiBoSS, that combines and extends two well-established tools: a signalling pathway modelling tool, MaBoSS [36,37], which performs stochastic simulations of the signalling pathway inside each cell, is integrated in an agent-based modelling tool, PhysiCell [38], that represents each individual cell as a physical dynamical entity.…”