Optimization of logical networks for the modelling of cancer signalling pathways

Cancer is one of the main causes of death throughout the world. The survival of patients diagnosed with various cancer types remains low despite the numerous progresses of the last decades. Some of the reasons for this unmet clinical need are the high heterogeneity between patients, the differentiation of cancer cells within a single tumor, the persistence of cancer stem cells, and the high number of possible clinical phenotypes arising from the combination of the genetic and epigenetic insults that confer to cells the functional characteristics enabling them to proliferate, evade the immune system and programmed cell death, and give rise to neoplasms. To identify new therapeutic options, a better understanding of the mechanisms that generate and maintain these functional characteristics is needed. As many of the alterations that characterize cancerous lesions relate to the signaling pathways that ensure the adequacy of cellular behavior in a specific micro-environment and in response to molecular cues, it is likely that increased knowledge about these signaling pathways will result in the identification of new pharmacological targets towards which new drugs can be designed. As such, the modeling of the cellular regulatory networks can play a prominent role in this understanding, as computational modeling allows the integration of large quantities of data and the simulation of large systems. Logical modeling is well adapted to the large-scale modeling of regulatory networks. Different types of logical network modeling have been used successfully to study cancer signaling pathways and investigate specific hypotheses. In this work we propose a Dynamic Bayesian Network framework to contextualize network models of signaling pathways. We implemented FALCON, a Matlab toolbox to formulate the parametrization of a prior-knowledge interaction network given a set of biological measurements under different experimental conditions. The FALCON toolbox allows a systems-level analysis of the model with the aim of identifying the most sensitive nodes and interactions of the inferred regulatory network and point to possible ways to modify its functional properties. The resulting hypotheses can be tested in the form of virtual knock-out experiments. We also propose a series of regularization schemes, materializing biological assumptions, to incorporate relevant research questions in the optimization procedure. These questions include the detection of the active signaling pathways in a specific context, the identification of the most important differences within a group of cell lines, or the time-frame of network rewiring. We used the toolbox and its extensions on a series of toy models and biological examples. We showed that our pipeline is able to identify cell type-specific parameters that are predictive of drug sensitivity, using a regularization scheme based on local parameter densities in the parameter space. We applied FALCON to the analysis of the resistance mechanism in A375 melanoma cells adapted to low doses of a TNFR agonist, and we accurately predict the re-sensitization and successful induction of apoptosis in the adapted cells via the silencing of XIAP and the down-regulation of NFkB. We further point to specific drug combinations that could be applied in the clinics. Overall, we demonstrate that our approach is able to identify the most relevant changes between sensitive and resistant cancer clones

Using Regularization to Infer Cell Line Specificity in Logical Network Models of Signaling Pathways.

Understanding the functional properties of cells of different origins is a long-standing challenge of personalized medicine. Especially in cancer, the high heterogeneity observed in patients slows down the development of effective cures. The molecular differences between cell types or between healthy and diseased cellular states are usually determined by the wiring of regulatory networks. Understanding these molecular and cellular differences at the systems level would improve patient stratification and facilitate the design of rational intervention strategies. Models of cellular regulatory networks frequently make weak assumptions about the distribution of model parameters across cell types or patients. These assumptions are usually expressed in the form of regularization of the objective function of the optimization problem. We propose a new method of regularization for network models of signaling pathways based on the local density of the inferred parameter values within the parameter space. Our method reduces the complexity of models by creating groups of cell line-specific parameters which can then be optimized together. We demonstrate the use of our method by recovering the correct topology and inferring accurate values of the parameters of a small synthetic model. To show the value of our method in a realistic setting, we re-analyze a recently published phosphoproteomic dataset from a panel of 14 colon cancer cell lines. We conclude that our method efficiently reduces model complexity and helps recovering context-specific regulatory information

FALCON: A Toolbox for the Fast Contextualisation of Logical Networks.

Motivation: Mathematical modelling of regulatory networks allows for the discovery of knowledge at the system level. However, existing modelling tools are often computation-heavy and do not offer intuitive ways to explore the model, to test hypotheses or to interpret the results biologically. Results: We have developed a computational approach to contextualise logical models of regulatory networks with biological measurements based on a probabilistic description of rule-based interactions between the different molecules. Here, we propose a Matlab toolbox, FALCON, to automatically and efficiently build and contextualise networks, which includes a pipeline for conducting parameter analysis, knockouts, and easy and fast model investigation. The contextualised models could then provide qualitative and quantitative information about the network and suggest hypotheses about biological processes. Availability and implementation: FALCON is freely available for non-commercial users on GitHub under the GPLv3 licence. The toolbox, installation instructions, full documentation and test datasets are available at https://github.com/sysbiolux/FALCON . FALCON runs under Matlab (MathWorks) and requires the Optimization Toolbox. Contact: [email protected]. Supplementary information: Supplementary data are available at Bioinformatics online

Stochastic simulation of HIV epidemic

<p>This is my masters thesis report, in which I model the HIV epidemic in Luxembourg with a high-level, realistic, stochastic simulation and make predictions for the future under different assumptions.</p

Topological network measures for drug repositioning.

Drug repositioning has received increased attention since the past decade as several blockbuster drugs have come out of repositioning. Computational approaches are significantly contributing to these efforts, of which, network-based methods play a key role. Various structural (topological) network measures have thereby contributed to uncovering unintuitive functional relationships and repositioning candidates in drug-disease and other networks. This review gives a broad overview of the topic, and offers perspectives on the application of topological measures for network analysis. It also discusses unexplored measures, and draws attention to a wider scope of application efforts, especially in drug repositioning

Construction and contextualization approaches for protein-protein interaction networks.

Protein-protein interaction network (PPIN) analysis is a widely used method to study the contextual role of proteins of interest, to predict novel disease genes, disease or functional modules, and to identify novel drug targets. PPIN-based analysis uses both generic and context-specific networks. Multiple contextualization methodologies have been described, such as shortest-path algorithms, neighborhood-based methods, and diffusion/propagation algorithms. This review discusses these methods, provides intuitive representations of PPIN contextualization, and also examines how the quality of such context-specific networks could be improved by considering additional sources of evidence. As a heuristic, we observe that tasks such as identifying disease genes, drug targets, and protein complexes should consider local neighborhoods, while uncovering disease mechanisms and discovering disease-pathways would gain from diffusion-based construction

Expanding the Disease Network of Glioblastoma Multiforme via Topological Analysis.

Glioblastoma multiforme (GBM), a grade IV glioma, is a challenging disease for patients and clinicians, with an extremely poor prognosis. These tumours manifest a high molecular heterogeneity, with limited therapeutic options for patients. Since GBM is a rare disease, sufficient statistically strong evidence is often not available to explore the roles of lesser-known GBM proteins. We present a network-based approach using centrality measures to explore some key, topologically strategic proteins for the analysis of GBM. Since network-based analyses are sensitive to changes in network topology, we analysed nine different GBM networks, and show that small but well-curated networks consistently highlight a set of proteins, indicating their likely involvement in the disease. We propose 18 novel candidates which, based on differential expression, mutation analysis, and survival analysis, indicate that they may play a role in GBM progression. These should be investigated further for their functional roles in GBM, their clinical prognostic relevance, and their potential as therapeutic targets