Cancer onset and progression: A genome-wide, nonlinear dynamical systems perspective on onconetworks

Qu, K.
Haidar, A. Abi
Fan, J.
Ensman, L.
Tuncay, Kağan
Jolly, M.
Ortoleva, P.
It is hypothesized that the many human cell types corresponding to multiple states is supported by an underlying nonlinear dynamical system (NDS) of transcriptional regulatory network (TRN) processes. This hypothesis is validated for epithelial cells whose TRN is found to support an extremely complex array of states that we term a "bifurcation nexus", for which we introduce a quantitative measure of complexity. The TRN used is constructed and analyzed by integrating a database of TRN information, cDNA microarray data analyzers, bioinformatics modules, a transcription/transiation/post-translation kinetic model, and NDS analysis software. Results of this genome-wide approach suggest that a cell can be induced to persist in one state or to transition between distinct states; apparently irreversible transitions can be reversed when the high dimensional space of extracellular and intracellular parameters is understood. As conditions change, certain cellular states (cell lines) are no longer supported, new ones emerge, and transitions (cell differentiation or death) occur. The accumulation of simulated point mutations (minor changes which individually are insignificant) lead to occasional dramatic transitions. The genome-wide scope of many of these transitions is shown to arise from the cross-linked TRN structure. These notions imply that studying individual oncogenes may not be sufficient to understand cancer; rather, "onconetworks" (subsets of strongly coupled genes supporting multiple cell states) should be considered. Our approach reveals several epithelial onconetworks, each involving oncogenes and anti-tumor and supporting genes.


USP32 regulates late endosomal transport and recycling through deubiquitylation of Rab7
Sapmaz, Aysegul; Berlin, Ilana; Bos, Erik; Wijdeven, Ruud H.; Janssen, Hans; Konietzny, Rebecca; Akkermans, Jimmy J.; Erson Bensan, Ayşe Elif; Koning, Roman; Kessler, Benedikt M.; Neefjes, Jacques; Ovaa, Huib (2019-03-29)
The endosomal system is a highly dynamic multifunctional organelle, whose complexity is regulated in part by reversible ubiquitylation. Despite the wide-ranging influence of ubiquitin in endosomal processes, relatively few enzymes utilizing ubiquitin have been described to control endosome integrity and function. Here we reveal the deubiquitylating enzyme (DUB) ubiquitin-specific protease 32 (USP32) as a powerful player in this context. Loss of USP32 inhibits late endosome (LE) transport and recycling of LE...
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Sarac, Oemer Sinan; Atalay, Mehmet Volkan; Atalay, Rengül (Public Library of Science (PLoS), 2010-08-31)
Functional protein annotation is an important matter for in vivo and in silico biology. Several computational methods have been proposed that make use of a wide range of features such as motifs, domains, homology, structure and physicochemical properties. There is no single method that performs best in all functional classification problems because information obtained using any of these features depends on the function to be assigned to the protein. In this study, we portray a novel approach that combines ...
Bayesian inference for the MAPK/ERK pathway by considering the dependency of the kinetic parameters
Purutçuoğlu Gazi, Vilda (Institute of Mathematical Statistics, 2008-01-01)
The MAPK/ERK pathway is one of the major signal transduction systems which regulates the cellular growth control of all eukaryotes like the cell proliferation and the apoptosis. Because of its importance in cellular lifecycle, it has been studied intensively, resulting in a number of qualitative descriptions of this regulatory mechanism. In this study we describe the MAPK/ERK pathway as an explicit set of reactions by combining different sources. Our reaction set takes into account the localization and diff...
Exponential stability of periodic solutions of recurrent neural networks with functional dependence on piecewise constant argument
Akhmet, Marat; Cengiz, Nur (The Scientific and Technological Research Council of Turkey, 2018-01-01)
In this study, we develop a model of recurrent neural networks with functional dependence on piecewise constant argument of generalized type. Using the theoretical results obtained for functional differential equations with piecewise constant argument, we investigate conditions for existence and uniqueness of solutions, bounded solutions, and exponential stability of periodic solutions. We provide conditions based on the parameters of the model.
Epigenetic Mechanisms Underlying the Dynamic Expression of Cancer-Testis Genes, PAGE2, -2B and SPANX-B, during Mesenchymal-to-Epithelial Transition
Yilmaz-Ozcan, Sinem; Sade, Asli; Kucukkaraduman, Baris; Kaygusuz, Yasemin; Senses, Kerem Mert; Banerjee, Sreeparna; GÜRE, ALİ OSMAY (Public Library of Science (PLoS), 2014-09-17)
Cancer-testis (CT) genes are expressed in various cancers but not in normal tissues other than in cells of the germline. Although DNA demethylation of promoter-proximal CpGs of CT genes is linked to their expression in cancer, the mechanisms leading to demethylation are unknown. To elucidate such mechanisms we chose to study the Caco-2 colorectal cancer cell line during the course of its spontaneous differentiation in vitro, as we found CT genes, in particular PAGE2, -2B and SPANX-B, to be up-regulated duri...
Citation Formats
K. Qu et al., “Cancer onset and progression: A genome-wide, nonlinear dynamical systems perspective on onconetworks,” JOURNAL OF THEORETICAL BIOLOGY, pp. 234–244, 2007, Accessed: 00, 2020. [Online]. Available: