BACKGROUND: Cancer is a complex, multiscale dynamical system, with interactions between tumor cells and non-cancerous host systems. Therapies act on this combined cancer-host system, sometimes with unexpected results. Systematic investigation of mechanistic computational models can augment traditional laboratory and clinical studies, helping identify the factors driving a treatment's success or failure. However, given the uncertainties regarding the underlying biology, these multiscale computational models can take many potential forms, in addition to encompassing high-dimensional parameter spaces. Therefore, the exploration of these models is computationally challenging. We propose that integrating two existing technologies-one to aid the construction of multiscale agent-based models, the other developed to enhance model exploration and optimization-can provide a computational means for high-throughput hypothesis testing, and eventually, optimization. RESULTS: In this paper, we introduce a high throughput computing (HTC) framework that integrates a mechanistic 3-D multicellular simulator (PhysiCell) with an extreme-scale model exploration platform (EMEWS) to investigate high-dimensional parameter spaces. We show early results in applying PhysiCell-EMEWS to 3-D cancer immunotherapy and show insights on therapeutic failure. We describe a generalized PhysiCell-EMEWS workflow for high-throughput cancer hypothesis testing, where hundreds or thousands of mechanistic simulations are compared against data-driven error metrics to perform hypothesis optimization. CONCLUSIONS: While key notational and computational challenges remain, mechanistic agent-based models and high-throughput model exploration environments can be combined to systematically and rapidly explore key problems in cancer. These high-throughput computational experiments can improve our understanding of the underlying biology, drive future experiments, and ultimately inform clinical practice.

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 and deploy across platforms. PhysiCell has been parallelized with OpenMP, and its performance scales linearly with the number of cells. Simulations up to 105-106 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 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 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.

MOTIVATION: Computational models of multicellular systems require solving systems of PDEs for release, uptake, decay and diffusion of multiple substrates in 3D, particularly when incorporating the impact of drugs, growth substrates and signaling factors on cell receptors and subcellular systems biology. RESULTS: We introduce BioFVM, a diffusive transport solver tailored to biological problems. BioFVM can simulate release and uptake of many substrates by cell and bulk sources, diffusion and decay in large 3D domains. It has been parallelized with OpenMP, allowing efficient simulations on desktop workstations or single supercomputer nodes. The code is stable even for large time steps, with linear computational cost scalings. Solutions are first-order accurate in time and second-order accurate in space. The code can be run by itself or as part of a larger simulator. AVAILABILITY AND IMPLEMENTATION: BioFVM is written in C ++ with parallelization in OpenMP. It is maintained and available for download at http://BioFVM.MathCancer.org and http://BioFVM.sf.net under the Apache License (v2.0). CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: Cellular differentiation during development is controlled by gene regulatory networks (GRNs). This complex process is always subject to gene expression noise. There is evidence suggesting that commonly seen patterns in GRNs, referred to as biological multistable switches, play an important role in creating the structure of lineage trees by providing stability to cell types. RESULTS: To explore this question a new methodology is developed and applied to study (a) the multistable switch-containing GRN for hematopoiesis and (b) a large set of random boolean networks (RBNs) in which multistable switches were embedded systematically. In this work, each network attractor is taken to represent a distinct cell type. The GRNs were seeded with one or two identical copies of each multistable switch and the effect of these additions on two key aspects of network dynamics was assessed. These properties are the barrier to movement between pairs of attractors (separation) and the degree to which one direction of movement between attractor pairs is favored over another (directionality). Both of these properties are instrumental in shaping the structure of lineage trees. We found that adding one multistable switch of any type had a modest effect on increasing the proportion of well-separated attractor pairs. Adding two identical switches of any type had a much stronger effect in increasing the proportion of well-separated attractors. Similarly, there was an increase in the frequency of directional transitions between attractor pairs when two identical multistable switches were added to GRNs. This effect on directionality was not observed when only one multistable switch was added. CONCLUSIONS: This work provides evidence that the occurrence of multistable switches in networks that control cellular differentiation contributes to the structure of lineage trees and to the stabilization of cell types.

Sorting by reversals is a simplified version of the genome rearrangement problem that seeks to discover the evolutionary relationship between different genomes, and is one of the many challenging problems in Bioinformatics. Solving the problem optimally has been proved to be NP-Hard and so a selection of approximation algorithms have been developed. In this paper a new mapping order is introduced to solve the problem of sorting unsigned permutations using a specialized multi-objective genetic algorithm. Our modified genetic algorithm uses a population with variable length individuals to maintain a worst time running time complexity of 0(n4log2n), where n is the problem size. The results show that this approach is more effective than the 3/2 heuristic method and previous genetic algorithm approaches.