Building multiscale models with PhysiBoSS, an agent-based modeling tool.

Multiscale models provide a unique tool for studying complex processes that study events occurring at different scales across space and time. In the context of biological systems, such models can simulate mechanisms happening at the intracellular level such as signaling, and at the extracellular level where cells communicate and coordinate with other cells. They aim to understand the impact of genetic or environmental deregulation observed in complex diseases, describe the interplay between a pathological tissue and the immune system, and suggest strategies to revert the diseased phenotypes. The construction of these multiscale models remains a very complex task, including the choice of the components to consider, the level of details of the processes to simulate, or the fitting of the parameters to the data. One additional difficulty is the expert knowledge needed to program these models in languages such as C++ or Python, which may discourage the participation of non-experts. Simplifying this process through structured description formalisms - coupled with a graphical interface - is crucial in making modeling more accessible to the broader scientific community, as well as streamlining the process for advanced users. This article introduces three examples of multiscale models which rely on the framework PhysiBoSS, an add-on of PhysiCell that includes intracellular descriptions as continuous time Boolean models to the agent-based approach. The article demonstrates how to easily construct such models, relying on PhysiCell Studio, the PhysiCell Graphical User Interface. A step-by-step tutorial is provided as a Supplementary Material and all models are provided at: https://physiboss.github.io/tutorial/.

PhysiCell Studio: a graphical tool to make agent-based modeling more accessible.

Defining a multicellular model can be challenging. There may be hundreds of parameters that specify the attributes and behaviors of objects. In the best case, the model will be defined using some format specification - a markup language - that will provide easy model sharing (and a minimal step toward reproducibility). PhysiCell is an open-source, physics-based multicellular simulation framework with an active and growing user community. It uses XML to define a model and, traditionally, users needed to manually edit the XML to modify the model. PhysiCell Studio is a tool to make this task easier. It provides a GUI that allows editing the XML model definition, including the creation and deletion of fundamental objects: cell types and substrates in the microenvironment. It also lets users build their model by defining initial conditions and biological rules, run simulations, and view results interactively. PhysiCell Studio has evolved over multiple workshops and academic courses in recent years, which has led to many improvements. There is both a desktop and cloud version. Its design and development has benefited from an active undergraduate and graduate research program. Like PhysiCell, the Studio is open-source software and contributions from the community are encouraged.

Modeling the extracellular matrix in cell migration and morphogenesis: a guide for the curious biologist.

The extracellular matrix (ECM) is a highly complex structure through which biochemical and mechanical signals are transmitted. In processes of cell migration, the ECM also acts as a scaffold, providing structural support to cells as well as points of potential attachment. Although the ECM is a well-studied structure, its role in many biological processes remains difficult to investigate comprehensively due to its complexity and structural variation within an organism. In tandem with experiments, mathematical models are helpful in refining and testing hypotheses, generating predictions, and exploring conditions outside the scope of experiments. Such models can be combined and calibrated with in vivo and in vitro data to identify critical cell-ECM interactions that drive developmental and homeostatic processes, or the progression of diseases. In this review, we focus on mathematical and computational models of the ECM in processes such as cell migration including cancer metastasis, and in tissue structure and morphogenesis. By highlighting the predictive power of these models, we aim to help bridge the gap between experimental and computational approaches to studying the ECM and to provide guidance on selecting an appropriate model framework to complement corresponding experimental studies.

PhysiCell Studio: a graphical tool to make agent-based modeling more accessible.

Defining a multicellular model can be challenging. There may be hundreds of parameters that specify the attributes and behaviors of objects. Hopefully the model will be defined using some format specification, e.g., a markup language, that will provide easy model sharing (and a minimal step toward reproducibility). PhysiCell is an open source, physics-based multicellular simulation framework with an active and growing user community. It uses XML to define a model and, traditionally, users needed to manually edit the XML to modify the model. PhysiCell Studio is a tool to make this task easier. It provides a graphical user interface that allows editing the XML model definition, including the creation and deletion of fundamental objects, e.g., cell types and substrates in the microenvironment. It also lets users build their model by defining initial conditions and biological rules, run simulations, and view results interactively. PhysiCell Studio has evolved over multiple workshops and academic courses in recent years which has led to many improvements. Its design and development has benefited from an active undergraduate and graduate research program. Like PhysiCell, the Studio is open source software and contributions from the community are encouraged.

Multiscale model of the different modes of cancer cell invasion.

MOTIVATION: Mathematical models of biological processes altered in cancer are built using the knowledge of complex networks of signaling pathways, detailing the molecular regulations inside different cell types, such as tumor cells, immune and other stromal cells. If these models mainly focus on intracellular information, they often omit a description of the spatial organization among cells and their interactions, and with the tumoral microenvironment. RESULTS: We present here a model of tumor cell invasion simulated with PhysiBoSS, a multiscale framework, which combines agent-based modeling and continuous time Markov processes applied on Boolean network models. With this model, we aim to study the different modes of cell migration and to predict means to block it by considering not only spatial information obtained from the agent-based simulation but also intracellular regulation obtained from the Boolean model.Our multiscale model integrates the impact of gene mutations with the perturbation of the environmental conditions and allows the visualization of the results with 2D and 3D representations. The model successfully reproduces single and collective migration processes and is validated on published experiments on cell invasion. In silico experiments are suggested to search for possible targets that can block the more invasive tumoral phenotypes. AVAILABILITY AND IMPLEMENTATION: https://github.com/sysbio-curie/Invasion_model_PhysiBoSS.

WebMaBoSS: A Web Interface for Simulating Boolean Models Stochastically.

WebMaBoSS is an easy-to-use web interface for conversion, storage, simulation and analysis of Boolean models that allows to get insight from these models without any specific knowledge of modeling or coding. It relies on an existing software, MaBoSS, which simulates Boolean models using a stochastic approach: it applies continuous time Markov processes over the Boolean network. It was initially built to fill the gap between Boolean and continuous formalisms, i.e., providing semi-quantitative results using a simple representation with a minimum number of parameters to fit. The goal of WebMaBoSS is to simplify the use and the analysis of Boolean models coping with two main issues: 1) the simulation of Boolean models of intracellular processes with MaBoSS, or any modeling tool, may appear as non-intuitive for non-experts; 2) the simulation of already-published models available in current model databases (e.g., Cell Collective, BioModels) may require some extra steps to ensure compatibility with modeling tools such as MaBoSS. With WebMaBoSS, new models can be created or imported directly from existing databases. They can then be simulated, modified and stored in personal folders. Model simulations are performed easily, results visualized interactively, and figures can be exported in a preferred format. Extensive model analyses such as mutant screening or parameter sensitivity can also be performed. For all these tasks, results are stored and can be subsequently filtered to look for specific outputs. This web interface can be accessed at the address: https://maboss.curie.fr/webmaboss/ and deployed locally using docker. This application is open-source under LGPL license, and available at https://github.com/sysbio-curie/WebMaBoSS.