Data-Driven Modeling of Breast Cancer Tumors Using Boolean Networks
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ABSTRACT:
SUBMITTER: Sgariglia D
PROVIDER: S-EPMC8564392 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A Boolean model is a simple, discrete and dynamic model without the need to consider the effects at the intermediate levels. However, little effort has been made into constructing activation, inhibition, and protein decay networks, which could indicate the direct roles of a gene (or its synthesized protein) as an activator or inhibitor of a target gene. Therefore, we propose to focus on the general Boolean functions at the subfunction level taking into account the effectiveness of protein decay, and further split the subfunctions into the activation and inhibition domains. As a consequence, we developed a novel data-driven Boolean model; namely, the Fundamental Boolean Model (FBM), to draw insights into gene activation, inhibition, and protein decay. This novel Boolean model provides an intuitive definition of activation and inhibition pathways and includes mechanisms to handle protein decay issues. To prove the concept of the novel model, we implemented a platform using R language, called FBNNet. Our experimental results show that the proposed FBM could explicitly display the internal connections of the mammalian cell cycle between genes separated into the connection types of activation, inhibition and protein decay. Moreover, the method we proposed to infer the gene regulatory networks for the novel Boolean model can be run in parallel and; hence, the computation cost is affordable. Finally, the novel Boolean model and related Fundamental Boolean Networks (FBNs) could show significant trajectories in genes to reveal how genes regulated each other over a given period. This new feature could facilitate further research on drug interventions to detect the side effects of a newly-proposed drug.
| S-EPMC6167558 | biostudies-literature
Project description:BACKGROUND: Various computational models have been of interest due to their use in the modelling of gene regulatory networks (GRNs). As a logical model, probabilistic Boolean networks (PBNs) consider molecular and genetic noise, so the study of PBNs provides significant insights into the understanding of the dynamics of GRNs. This will ultimately lead to advances in developing therapeutic methods that intervene in the process of disease development and progression. The applications of PBNs, however, are hindered by the complexities involved in the computation of the state transition matrix and the steady-state distribution of a PBN. For a PBN with n genes and N Boolean networks, the complexity to compute the state transition matrix is O(nN22n) or O(nN2n) for a sparse matrix. RESULTS: This paper presents a novel implementation of PBNs based on the notions of stochastic logic and stochastic computation. This stochastic implementation of a PBN is referred to as a stochastic Boolean network (SBN). An SBN provides an accurate and efficient simulation of a PBN without and with random gene perturbation. The state transition matrix is computed in an SBN with a complexity of O(nL2n), where L is a factor related to the stochastic sequence length. Since the minimum sequence length required for obtaining an evaluation accuracy approximately increases in a polynomial order with the number of genes, n, and the number of Boolean networks, N, usually increases exponentially with n, L is typically smaller than N, especially in a network with a large number of genes. Hence, the computational efficiency of an SBN is primarily limited by the number of genes, but not directly by the total possible number of Boolean networks. Furthermore, a time-frame expanded SBN enables an efficient analysis of the steady-state distribution of a PBN. These findings are supported by the simulation results of a simplified p53 network, several randomly generated networks and a network inferred from a T cell immune response dataset. An SBN can also implement the function of an asynchronous PBN and is potentially useful in a hybrid approach in combination with a continuous or single-molecule level stochastic model. CONCLUSIONS: Stochastic Boolean networks (SBNs) are proposed as an efficient approach to modelling gene regulatory networks (GRNs). The SBN approach is able to recover biologically-proven regulatory behaviours, such as the oscillatory dynamics of the p53-Mdm2 network and the dynamic attractors in a T cell immune response network. The proposed approach can further predict the network dynamics when the genes are under perturbation, thus providing biologically meaningful insights for a better understanding of the dynamics of GRNs. The algorithms and methods described in this paper have been implemented in Matlab packages, which are attached as Additional files.
| S-EPMC3532238 | biostudies-literature
Project description:Cancer is a genetic disease for which traditional treatments cause harmful side effects. After two decades of genomics technological breakthroughs, personalized medicine is being used to improve treatment outcomes and mitigate side effects. In mathematical modeling, it has been proposed that cancer matches an attractor in Waddington's epigenetic landscape. The use of Hopfield networks is an attractive modeling approach because it requires neither previous biological knowledge about protein-protein interactions nor kinetic parameters. In this report, Hopfield network modeling was used to analyze bulk RNA-Seq data of paired breast tumor and control samples from 70 patients. We characterized the control and tumor attractors with respect to their size and potential energy and correlated the Euclidean distances between the tumor samples and the control attractor with their corresponding clinical data. In addition, we developed a protocol that outlines the key genes involved in tumor state stability. We found that the tumor basin of attraction is larger than that of the control and that tumor samples are associated with a more substantial negative energy than control samples, which is in agreement with previous reports. Moreover, we found a negative correlation between the Euclidean distances from tumor samples to the control attractor and patient overall survival. The ascending order of each node's density in the weight matrix and the descending order of the number of patients that have the target active only in the tumor sample were the parameters that withdrew more tumor samples from the tumor basin of attraction with fewer gene inhibitions. The combinations of therapeutic targets were specific to each patient. We performed an initial validation through simulation of trastuzumab treatment effects in HER2+ breast cancer samples. For that, we built an energy landscape composed of single-cell and bulk RNA-Seq data from trastuzumab-treated and non-treated HER2+ samples. The trajectory from the non-treated bulk sample toward the treated bulk sample was inferred through the perturbation of differentially expressed genes between these samples. Among them, we characterized key genes involved in the trastuzumab response according to the literature.
| S-EPMC7154169 | biostudies-literature
Project description:Multicellular tumor spheroid (MCTS) systems provide an in vitro cell culture model system which mimics many of the complexities of an in vivo solid tumor and tumor microenvironment, and are often used to study cancer cell growth and drug efficacy. Here, we present a coupled experimental-computational framework to estimate phenotypic growth and biophysical tumor microenvironment properties. This novel framework utilizes standard microscopy imaging of MCTS systems to drive a biophysical mathematical model of MCTS growth and mechanical interactions. By extending our previous in vivo mechanically-coupled reaction-diffusion modeling framework we developed a microscopy image processing framework capable of mechanistic characterization of MCTS systems. Using MDA-MB-231 breast cancer MCTS, we estimated biophysical parameters of cellular diffusion, rate of cellular proliferation, and cellular tractions forces. We found significant differences in these model-based biophysical parameters throughout the treatment time course between untreated and treated MCTS systems, whereas traditional size-based morphometric parameters were inconclusive. The proposed experimental-computational framework estimates mechanistic MCTS growth and invasion parameters with significant potential to assist in better and more precise assessment of in vitro drug efficacy through the development of computational analysis methodologies for three-dimensional cell culture systems to improve the development and evaluation of antineoplastic drugs.
| S-EPMC7360601 | biostudies-literature
Project description:BACKGROUND: Qualitative dynamics of small gene regulatory networks have been studied in quite some details both with synchronous and asynchronous analysis. However, both methods have their drawbacks: synchronous analysis leads to spurious attractors and asynchronous analysis lacks computational efficiency, which is a problem to simulate large networks. We addressed this question through the analysis of a major biosynthesis pathway. Indeed the cholesterol synthesis pathway plays a pivotal role in dislypidemia and, ultimately, in cancer through intermediates such as mevalonate, farnesyl pyrophosphate and geranyl geranyl pyrophosphate, but no dynamic model of this pathway has been proposed until now. RESULTS: We set up a computational framework to dynamically analyze large biological networks. This framework associates a classical and computationally efficient synchronous Boolean analysis with a newly introduced method based on Markov chains, which identifies spurious cycles among the results of the synchronous simulation. Based on this method, we present here the results of the analysis of the cholesterol biosynthesis pathway and its physiological regulation by the Sterol Response Element Binding Proteins (SREBPs), as well as the modeling of the action of statins, inhibitor drugs, on this pathway. The in silico experiments show the blockade of the cholesterol endogenous synthesis by statins and its regulation by SREPBs, in full agreement with the known biochemical features of the pathway. CONCLUSION: We believe that the method described here to identify spurious cycles opens new routes to compute large and biologically relevant models, thanks to the computational efficiency of synchronous simulation. Furthermore, to the best of our knowledge, we present here the first dynamic systems biology model of the human cholesterol pathway and several of its key regulatory control elements, hoping it would provide a good basis to perform in silico experiments and confront the resulting properties with published and experimental data. The model of the cholesterol pathway and its regulation, along with Boolean formulae used for simulation are available on our web site http://Bioinformaticsu613.free.fr. Graphical results of the simulation are also shown online. The SBML model is available in the BioModels database http://www.ebi.ac.uk/biomodels/ with submission ID: MODEL0568648427.
| S-EPMC2612667 | biostudies-literature
Project description:BackgroundA popular model for gene regulatory networks is the Boolean network model. In this paper, we propose an algorithm to perform an analysis of gene regulatory interactions using the Boolean network model and time-series data. Actually, the Boolean network is restricted in the sense that only a subset of all possible Boolean functions are considered. We explore some mathematical properties of the restricted Boolean networks in order to avoid the full search approach. The problem is modeled as a Constraint Satisfaction Problem (CSP) and CSP techniques are used to solve it.ResultsWe applied the proposed algorithm in two data sets. First, we used an artificial dataset obtained from a model for the budding yeast cell cycle. The second data set is derived from experiments performed using HeLa cells. The results show that some interactions can be fully or, at least, partially determined under the Boolean model considered.ConclusionsThe algorithm proposed can be used as a first step for detection of gene/protein interactions. It is able to infer gene relationships from time-series data of gene expression, and this inference process can be aided by a priori knowledge available.
| S-EPMC3090763 | biostudies-literature
Project description:Boolean implications (if-then rules) provide a conceptually simple, uniform and highly scalable way to find associations between pairs of random variables. In this paper, we propose to use Boolean implications to find relationships between variables of different data types (mutation, copy number alteration, DNA methylation and gene expression) from the glioblastoma (GBM) and ovarian serous cystadenoma (OV) data sets from The Cancer Genome Atlas (TCGA). We find hundreds of thousands of Boolean implications from these data sets. A direct comparison of the relationships found by Boolean implications and those found by commonly used methods for mining associations show that existing methods would miss relationships found by Boolean implications. Furthermore, many relationships exposed by Boolean implications reflect important aspects of cancer biology. Examples of our findings include cis relationships between copy number alteration, DNA methylation and expression of genes, a new hierarchy of mutations and recurrent copy number alterations, loss-of-heterozygosity of well-known tumor suppressors, and the hypermethylation phenotype associated with IDH1 mutations in GBM. The Boolean implication results used in the paper can be accessed at http://crookneck.stanford.edu/microarray/TCGANetworks/.
| S-EPMC4108374 | biostudies-literature
Project description:Understanding relationships among multimodal data extracted from a smartphone-based electrochemiluminescence (ECL) sensor is crucial for the development of low-cost point-of-care diagnostic devices. In this work, artificial intelligence (AI) algorithms such as random forest (RF) and feedforward neural network (FNN) are used to quantitatively investigate the relationships between the concentration of Ru(bpy)32+ luminophore and its experimentally measured ECL and electrochemical data. A smartphone-based ECL sensor with Ru(bpy)32+/TPrA was developed using disposable screen-printed carbon electrodes. ECL images and amperograms were simultaneously obtained following 1.2-V voltage application. These multimodal data were analyzed by RF and FNN algorithms, which allowed the prediction of Ru(bpy)32+ concentration using multiple key features. High correlation (0.99 and 0.96 for RF and FNN, respectively) between actual and predicted values was achieved in the detection range between 0.02 µM and 2.5 µM. The AI approaches using RF and FNN were capable of directly inferring the concentration of Ru(bpy)32+ using easily observable key features. The results demonstrate that data-driven AI algorithms are effective in analyzing the multimodal ECL sensor data. Therefore, these AI algorithms can be an essential part of the modeling arsenal with successful application in ECL sensor data modeling.
| S-EPMC7038330 | biostudies-literature
Project description:The molecular regulatory network (MRN) within a cell determines cellular states and transitions between them. Thus, modeling of MRNs is crucial, but this usually requires extensive analysis of time-series measurements, which is extremely difficult to obtain from biological experiments. However, single-cell measurement data such as single-cell RNA-sequencing databases have recently provided a new insight into resolving this problem by ordering thousands of cells in pseudo-time according to their differential gene expressions. Neural network modeling can be employed by using temporal data as learning data. In contrast, Boolean network modeling of MRNs has a growing interest, as it is a parameter-free logical modeling and thereby robust to noisy data while still capturing essential dynamics of biological networks. In this study, we propose a Boolean feedforward neural network (FFN) modeling by combining neural network and Boolean network modeling approach to reconstruct a practical and useful MRN model from large temporal data. Furthermore, analyzing the reconstructed MRN model can enable us to identify control targets for potential cellular state conversion. Here, we show the usefulness of Boolean FFN modeling by demonstrating its applicability through a toy model and biological networks.
| S-EPMC7736109 | biostudies-literature
Project description:Network modeling plays a critical role in identifying statistical regularities and structural principles common to many systems. The large majority of recent modeling approaches are connectivity driven. The structural patterns of the network are at the basis of the mechanisms ruling the network formation. Connectivity driven models necessarily provide a time-aggregated representation that may fail to describe the instantaneous and fluctuating dynamics of many networks. We address this challenge by defining the activity potential, a time invariant function characterizing the agents' interactions and constructing an activity driven model capable of encoding the instantaneous time description of the network dynamics. The model provides an explanation of structural features such as the presence of hubs, which simply originate from the heterogeneous activity of agents. Within this framework, highly dynamical networks can be described analytically, allowing a quantitative discussion of the biases induced by the time-aggregated representations in the analysis of dynamical processes.
| S-EPMC3384079 | biostudies-other