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  • 1
    Keywords: CANCER ; EXPRESSION ; CELL ; Germany ; KINASE ; MODEL ; PATHWAY ; CLASSIFICATION ; SUPPORT ; SYSTEM ; SYSTEMS ; GENE ; GENE-EXPRESSION ; PROTEIN ; MICE ; ACTIVATION ; animals ; RATS ; BIOLOGY ; fibroblasts ; PHOSPHORYLATION ; PROTEIN-KINASE ; SEQUENCE ; gene expression ; HUMANS ; PROMOTER ; REQUIRES ; SIGNALING PATHWAY ; DOSE-RESPONSE ; TRANSFORMATION ; PREDICTION ; KINETICS ; SELECTION ; REVEALS ; systems biology ; BEHAVIOR ; Ras ; signaling ; MAPK ; regulation ; mRNA ; PHOSPHATASE ; EXTENT ; Oligonucleotide Array Sequence Analysis ; RNA Stability ; INVESTIGATE ; Extracellular ; cellular response ; CELLULAR-RESPONSE ; SEQUENCE DATA ; hypothesis ; *Genes,ras ; *Models,Biological ; Cells,Cultured ; *Feedback,Biochemical ; Dual Specificity Phosphatase 6/*physiology ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Fibroblasts/metabolism ; MAP Kinase Signaling System/physiology ; RNA,Messenger/metabolism ; Signal Transduction/physiology
    Abstract: Mitogen-activated protein kinase (MAPK) signaling determines crucial cell fate decisions in most cell types, and mediates cellular transformation in many types of cancer. The activity of MAPK is controlled by reversible phosphorylation, and the quantitative characteristics of MAPK activation determine the cellular response. Many systems biological studies have analyzed the activation kinetics and the dose-response behavior of the MAPK signaling pathway. Here we investigate how the pathway activity is controlled by transcriptional feedback loops. Initially, we predict that MAPK signaling regulates phosphatases, by integrating promoter sequence data and ontology-based classification of gene function. From this, we deduce that MAPK signaling might be controlled by transcriptional negative feedback regulation via dual-specificity phosphatases (DUSPs), and implement a mathematical model to further test this hypothesis. Using time-resolved measurements of pathway activity and gene expression, we employ a model selection approach, and select DUSP6 as a highly likely candidate for shaping the activity of the MAPK pathway during cellular transformation caused by oncogenic RAS. Two predictions from the model were confirmed: first, feedback regulation requires that DUSP6 mRNA and protein are unstable; and second, the activation kinetics of MAPK are ultrasensitive. Taken together, an integrated systems biological approach reveals that transcriptional negative feedback controls the kinetics and the extent of MAPK activation under both physiological and pathological conditions.
    Type of Publication: Journal article published
    PubMed ID: 19154344
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  • 2
    Keywords: GENE ; TUMOR PROGRESSION ; B-RAF ; ACQUIRED-RESISTANCE ; COLORECTAL-CANCER CELLS ; senescence ; SELF-RENEWAL ; WNT/BETA-CATENIN ; HUMAN COLON ; SERRATED PATHWAY
    Abstract: Colon cancer cells frequently carry mutations that activate the beta-catenin and mitogen-activated protein kinase (MAPK) signaling cascades. Yet how oncogenic alterations interact to control cellular hierarchies during tumor initiation and progression is largely unknown. We found that oncogenic BRAF modulates gene expression associated with cell differentiation in colon cancer cells. We therefore engineered a mouse with an inducible oncogenic BRAF transgene, and analyzed BRAF effects on cellular hierarchies in the intestinal epithelium in vivo and in primary organotypic culture. We demonstrate that transgenic expression of oncogenic BRAF in the mouse strongly activated MAPK signal transduction, resulted in the rapid development of generalized serrated dysplasia, but unexpectedly also induced depletion of the intestinal stem cell (ISC) pool. Histological and gene expression analyses indicate that ISCs collectively converted to short-lived progenitor cells after BRAF activation. As Wnt/beta-catenin signals encourage ISC identity, we asked whether beta-catenin activity could counteract oncogenic BRAF. Indeed, we found that intestinal organoids could be partially protected from deleterious oncogenic BRAF effects by Wnt3a or by small-molecule inhibition of GSK3beta. Similarly, transgenic expression of stabilized beta-catenin in addition to oncogenic BRAF partially prevented loss of stem cells in the mouse intestine. We also used BRAFV637E knock-in mice to follow changes in the stem cell pool during serrated tumor progression and found ISC marker expression reduced in serrated hyperplasia forming after BRAF activation, but intensified in progressive dysplastic foci characterized by additional mutations that activate the Wnt/beta-catenin pathway. Our study suggests that oncogenic alterations activating the MAPK and Wnt/beta-catenin pathways must be consecutively and coordinately selected to assure stem cell maintenance during colon cancer initiation and progression. Notably, loss of stem cell identity upon induction of BRAF/MAPK activity may represent a novel fail-safe mechanism protecting intestinal tissue from oncogene activation.Oncogene advance online publication, 11 August 2014; doi:10.1038/onc.2014.247.
    Type of Publication: Journal article published
    PubMed ID: 25109331
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  • 3
    Keywords: TUMOR PROGRESSION ; SIGNALING PATHWAY ; COLON-CANCER ; K-RAS ; B-RAF ; ACQUIRED-RESISTANCE ; ISLAND METHYLATOR PHENOTYPE ; INTESTINAL STEM-CELLS ; MOLECULAR-FEATURES ; RAS GENE-MUTATIONS
    Abstract: Colorectal cancer (CRC) is characterized by recurrent mutations deregulating key cell signaling cascades and providing the cancer cells with novel functional traits. Among the most frequent mutations in CRC are gain-of-function missense mutations in KRAS and BRAF. Oncogenic activation of KRAS and BRAF is mutually exclusive and occurs in approximately 40% and 10% of all CRCs, respectively. Here we summarize genetic alterations currently described in the literature and databases, indicating overlapping but also specific co-occurrences with either mutated BRAF or KRAS. We describe common and potentially specific biological functions of KRAS and BRAF oncoproteins in the intestinal epithelial cells and during initiation and progression of CRC. We discuss signal transduction networks, highlighting individual functions of oncogenic KRAS and BRAF in terms of feedback loops and their impact on treatment outcome. Finally, we give an update on current strategies of targeted therapeutic intervention in oncogenic RAS-RAF signaling networks for the treatment of metastatic CRC and outline future directions.
    Type of Publication: Journal article published
    PubMed ID: 26299805
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  • 4
    Abstract: MOTIVATION: Integrating heterogeneous datasets from several sources is a common bioinformatics task that often requires implementing a complex workflow intermixing database access, data filtering, format conversions, identifier mapping, among further diverse operations. Data integration is especially important when annotating next generation sequencing data, where a multitude of diverse tools and heterogeneous databases can be used to provide a large variety of annotation for genomic locations, such a single nucleotide variants or genes. Each tool and data source is potentially useful for a given project and often more than one are used in parallel for the same purpose. However, software that always produces all available data is difficult to maintain and quickly leads to an excess of data, creating an information overload rather than the desired goal-oriented and integrated result. RESULTS: We present SoFIA, a framework for workflow-driven data integration with a focus on genomic annotation. SoFIA conceptualizes workflow templates as comprehensive workflows that cover as many data integration operations as possible in a given domain. However, these templates are not intended to be executed as a whole; instead, when given an integration task consisting of a set of input data and a set of desired output data, SoFIA derives a minimal workflow that completes the task. These workflows are typically fast and create exactly the information a user wants without requiring them to do any implementation work. Using a comprehensive genome annotation template, we highlight the flexibility, extensibility and power of the framework using real-life case studies. AVAILABILITY AND IMPLEMENTATION: https://github.com/childsish/sofia/releases/latest under the GNU General Public License CONTACT: liam.childs@hu-berlin.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    Type of Publication: Journal article published
    PubMed ID: 27187206
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  • 5
    Abstract: Here we study the effects of inducible oncogenic K-Ras (G12V) expression on the polarized morphogenesis of colonic epithelial cells. We provide evidence that the autocrine production of heregulins, ligands for the ErbB3 receptor tyrosine kinase, is responsible for the hyperproliferation and aberrant 3D morphogenesis upon oncogenic K-Ras expression. This is in line with results obtained in primary intestinal organoid cultures, in which exogenous heregulin is shown to interfere with normal tissue architecture. Importantly, ErbB3 inhibition and heregulin gene silencing rescued K-RasG12V-induced features of cell transformation. Together with the increased ErbB3 positivity detected in human high-grade primary colorectal cancers, our findings provide support for an autocrine signaling loop engaged by oncogenic K-Ras involving ErbB3 that contributes to the dedifferentiation of the intestinal epithelium during tumor initiation and progression.
    Type of Publication: Journal article published
    PubMed ID: 27447549
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  • 6
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  133. Kongress der Deutschen Gesellschaft für Chirurgie; 20160426-20160429; Berlin; DOC16dgch397 /20160421/
    Publication Date: 2016-04-22
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 7
    Keywords: EXPRESSION ; IN-VITRO ; proliferation ; Germany ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; VITRO ; PROTEIN ; ACTIVATION ; MACROPHAGES ; MECHANISM ; INDUCTION ; mechanisms ; DYNAMICS ; BIOLOGY ; PROTEIN-KINASE ; SIGNAL ; cytokines ; TRANSCRIPTION FACTORS ; PROMOTER ; SIGNAL-TRANSDUCTION ; immune response ; systems biology ; CYTOKINE ; molecular biology ; MAPK ; regulation ; USA ; macrophage ; INTERLEUKIN-10 ; ERK ACTIVATION ; STATE ; KINASE ACTIVATION ; TRANSIENT ; autocrine crosstalk ; host-parasite interaction ; IL-10 GENE-EXPRESSION ; signalling cascades
    Abstract: Parasitic nematodes can downregulate the immune response of their hosts through the induction of immunoregulatory cytokines such as interleukin-10 (IL-10). To define the underlying mechanisms, we measured in vitro the production of IL-10 in macrophages in response to cystatin from Acanthocheilonema viteae, an immunomodulatory protein of filarial nematodes, and developed mathematical models of IL-10 regulation. IL-10 expression requires stimulation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and p38, and we propose that a negative feedback mechanism, acting at the signalling level, is responsible for transient IL-10 production that can be followed by a sustained plateau. Specifically, a model with negative feedback on the ERK pathway via secreted IL-10 accounts for the experimental data. Accordingly, the model predicts sustained phospho-p38 dynamics, whereas ERK activation changes from transient to sustained when the concentration of immunomodulatory protein of Acanthocheilonema viteae increases. We show that IL-10 can regulate its own production in an autocrine fashion, and that ERK and p38 control IL-10 amplitude, duration and steady state. We also show that p38 affects ERK via secreted IL-10 (autocrine crosstalk). These findings demonstrate how convergent signalling pathways may differentially control kinetic properties of the IL-10 signal
    Type of Publication: Journal article published
    PubMed ID: 19456864
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  • 8
    Keywords: ACTIVATION, ANTIGEN, assembly, CANCER, CANCER CELLS, CANCER-CELLS, CELL, CELLS, COLON-CANCER, colore
    Abstract: Most malignant features of cancer cells are triggered by activated oncogenes and the loss of tumor suppressors due to mutation or epigenetic inactivation. It is still unclear, to what extend the escape of emerging cancer cells from recognition and elimination by the immune system is determined by similar mechanisms. We compared the transcriptomes of HCT116 colorectal cancer cells deficient in DNA methyltransferases (DNMTs) and of cells, in which the RAS pathway as the major growth-promoting signaling system is blocked by inhibition of MAPK. We identified the MHC Class I genes HLA-A1/A2 and the ULBP2 gene encoding 1 of the 8 known ligands of the activating NK receptor NKG2D among a cluster of immune genes up-regulated under the conditions of both DNMT-deficiency and MEK-inhibition. Bisulphite sequencing analyses of HCT116 with DNMT deficiency or after MEK-inhibition showed that de-methylation of the ULPB2 promoter correlated with its enhanced surface expression. The HLA-A promoters were not methylated indicating that components of the HLA assembly machinery were also suppressed in DNMT-deficient and MEK-inhibited cells. Increased HLA-A2 surface expression was correlated with enhanced recognition and lysis by A2-specific CTL. On the contrary, elevated ULBP2 expression was not reflected by enhanced recognition and lysis by NK cells. Cosuppression of HLA Class I and NKG2D ligands and genes encoding peptide transporters or proteasomal genes mediates a strong functional link between RAS activation, DNMT activity and disruption of the antigen presenting system controlling immune recognition in colorectal cancer cells. (C) 2009 UICC
    Type of Publication: Journal article published
    PubMed ID: 19569244
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  • 9
    Keywords: EXPRESSION ; IN-VIVO ; GENES ; METABOLISM ; CELL-CYCLE ; TUMOR PROGRESSION ; COLORECTAL-CANCER ; REGULATORY ELEMENTS ; DNA-DAMAGE RESPONSE ; RHYTHMS
    Abstract: Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARgamma, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.
    Type of Publication: Journal article published
    PubMed ID: 24875049
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  • 10
    Keywords: GENOME ; INSTABILITY ; EVOLUTION ; SELECTION ; RECTAL-CANCER ; CONSEQUENCES ; TARGETED THERAPY ; HUMAN COLON ; INTRATUMOR HETEROGENEITY ; MATCHED PRIMARY
    Abstract: A multistep model of disease progression and genomic landscape has been firmly established for colorectal cancer (CRC) primaries, but the genetic makeup of related metastases and the dynamics of genetic changes during metastatic progression are scarcely known. To address these issues, we used multigene high-coverage next-generation sequencing of 24 microsatellite-stable CRC primaries, matched normal tissue, and related multiple metastases to nodes, liver, lung, and brain with a CRC-specific gene panel to infer the degree of clonal evolution during metastatic progression of the disease. Somatic mutations were detected in 40% of CRC-related genes, and we observed a striking 100% genetic concordance between primary and multiple secondary sites for APC, KRAS, FBXW7, PIK3CA, BRAF, SMAD4, and ACVR2A. Except for true de novo mutations in 4 cases (affecting SYNE1, CTNNB1, TP53, and PTEN), all remaining cases (84.4%) shared the genetic lesions of the primary tumors with all investigated metastases irrespective of the site of metastasis or time lapse between primary tumor resection and the occurrence of metastatic spread. Putative biomarkers and druggable targets were identified in 25% of the cases. Our data proves that genetic alterations occurring early in CRC carcinogenesis are remarkably stable during metastatic progression, indicating (i) a very low degree of genetic heterogeneity between primary and multiple secondary sites with respect to CRC driver mutations and (ii) that genetic interrogation of archived primary tumor samples appears to be sufficient for the application of cancer precision medicine in the metastatic setting.
    Type of Publication: Journal article published
    PubMed ID: 25786087
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