Quantitative modeling of signaling in aggressive B cell lymphoma unveils conserved core network.

B cell receptor (BCR) signaling is required for the survival and maturation of B cells and is deregulated in B cell lymphomas. While proximal BCR signaling is well studied, little is known about the crosstalk of downstream effector pathways, and a comprehensive quantitative network analysis of BCR signaling is missing. Here, we semi-quantitatively modelled BCR signaling in Burkitt lymphoma (BL) cells using systematically perturbed phosphorylation data of BL-2 and BL-41 cells.

Combination of tumor asphericity and an extracellular matrix-related prognostic gene signature in non-small cell lung cancer patients.

One important aim of precision oncology is a personalized treatment of patients. This can be achieved by various biomarkers, especially imaging parameters and gene expression signatures are commonly used. So far, combination approaches are sparse.

Modeling unveils sex differences of signaling networks in mouse embryonic stem cells.

For a short period during early development of mammalian embryos, both X chromosomes in females are active, before dosage compensation is ensured through X-chromosome inactivation. In female mouse embryonic stem cells (mESCs), which carry two active X chromosomes, increased X-dosage affects cell signaling and impairs differentiation. The underlying mechanisms, however, remain poorly understood.

Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance.

Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and mathematical modelling, we determined potential resistance mechanisms.

Mutation-specific effects of NRAS oncogenes in colorectal cancer cells.

In colorectal cancer (CRC), the prevalence of NRAS mutations (5-9%) is inferior to that of KRAS mutations (40-50%). NRAS mutations feature lately during tumour progression and drive resistance to anti-EGFR therapy in KRAS wild-type tumours. To elucidate specific functions of NRAS mutations in CRC, we expressed doxycycline-inducible G12D and Q61K mutations in the CRC cell line Caco-2.

Neuronal activity regulates alternative exon usage.

Neuronal activity-regulated gene transcription underlies plasticity-dependent changes in the molecular composition and structure of neurons. A large number of genes regulated by different neuronal plasticity inducing pathways have been identified, but altered gene expression levels represent only part of the complexity of the activity-regulated transcriptional program. Alternative splicing, the differential inclusion and exclusion of exonic sequence in mRNA, is an additional mechanism that is thought to define the activity-dependent transcriptome.

SFPQ Depletion Is Synthetically Lethal with BRAF in Colorectal Cancer Cells.

Oncoproteins such as the BRAF kinase endow cancer cells with malignant properties, but they also create unique vulnerabilities. Targeting of BRAF-driven cytoplasmic signaling networks has proved ineffective, as patients regularly relapse with reactivation of the targeted pathways. We identify the nuclear protein SFPQ to be synthetically lethal with BRAF in a loss-of-function shRNA screen.

Reduced replication origin licensing selectively kills KRAS-mutant colorectal cancer cells via mitotic catastrophe.

To unravel vulnerabilities of KRAS-mutant CRC cells, a shRNA-based screen specifically inhibiting MAPK pathway components and targets was performed in CaCo2 cells harboring conditional oncogenic KRAS. The custom-designed shRNA library comprised 121 selected genes, which were previously identified to be strongly regulated in response to MEK inhibition. The screen showed that CaCo2 cells expressing KRAS were sensitive to the suppression of the DNA replication licensing factor minichromosome maintenance complex component 7 (MCM7), whereas KRAS CaCo2 cells were largely resistant to MCM7 suppression.

SPEED2: inferring upstream pathway activity from differential gene expression.

Extracting signalling pathway activities from transcriptome data is important to infer mechanistic origins of transcriptomic dysregulation, for example in disease. A popular method to do so is by enrichment analysis of signature genes in e.g.

Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium.

Oncogenic mutations in KRAS or BRAF are frequent in colorectal cancer and activate the ERK kinase. Here, we find graded ERK phosphorylation correlating with cell differentiation in patient-derived colorectal cancer organoids with and without KRAS mutations. Using reporters, single cell transcriptomics and mass cytometry, we observe cell type-specific phosphorylation of ERK in response to transgenic KRAS in mouse intestinal organoids, while transgenic BRAF activates ERK in all cells.

The cancer cell proteome and transcriptome predicts sensitivity to targeted and cytotoxic drugs.

Tumors of different molecular subtypes can show strongly deviating responses to drug treatment, making stratification of patients based on molecular markers an important part of cancer therapy. Pharmacogenomic studies have led to the discovery of selected genomic markers (e.g.

Isoform-specific Ras signaling is growth factor dependent.

HRAS, NRAS, and KRAS isoforms are almost identical proteins that are ubiquitously expressed and activate a common set of effectors. In vivo studies have revealed that they are not biologically redundant; however, the isoform specificity of Ras signaling remains poorly understood. Using a novel panel of isogenic SW48 cell lines endogenously expressing wild-type or G12V-mutated activated Ras isoforms, we have performed a detailed characterization of endogenous isoform-specific mutant Ras signaling.

Comparative Network Reconstruction using mixed integer programming.

Motivation: Signal-transduction networks are often aberrated in cancer cells, and new anti-cancer drugs that specifically target oncogenes involved in signaling show great clinical promise. However, the effectiveness of such targeted treatments is often hampered by innate or acquired resistance due to feedbacks, crosstalks or network adaptations in response to drug treatment. A quantitative understanding of these signaling networks and how they differ between cells with different oncogenic mutations or between sensitive and resistant cells can help in addressing this problem.

Reverse engineering gene regulatory networks by modular response analysis - a benchmark.

Gene regulatory networks control the cellular phenotype by changing the RNA and protein composition. Despite its importance, the gene regulatory network in higher organisms is only partly mapped out. Here, we investigate the potential of reverse engineering methods to unravel the structure of these networks.

Modelling signalling networks from perturbation data.

Motivation: Intracellular signalling is realized by complex signalling networks, which are almost impossible to understand without network models, especially if feedbacks are involved. Modular Response Analysis (MRA) is a convenient modelling method to study signalling networks in various contexts.

Results: We developed the software package STASNet (STeady-STate Analysis of Signalling Networks) that provides an augmented and extended version of MRA suited to model signalling networks from incomplete perturbation schemes and multi-perturbation data.

Perturbation-response genes reveal signaling footprints in cancer gene expression.

Aberrant cell signaling can cause cancer and other diseases and is a focal point of drug research. A common approach is to infer signaling activity of pathways from gene expression. However, mapping gene expression to pathway components disregards the effect of post-translational modifications, and downstream signatures represent very specific experimental conditions.

An immediate-late gene expression module decodes ERK signal duration.

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An immediate-late gene expression module decodes ERK signal duration.

The RAF-MEK-ERK signalling pathway controls fundamental, often opposing cellular processes such as proliferation and apoptosis. Signal duration has been identified to play a decisive role in these cell fate decisions. However, it remains unclear how the different early and late responding gene expression modules can discriminate short and long signals.

Drug Resistance Mechanisms in Colorectal Cancer Dissected with Cell Type-Specific Dynamic Logic Models.

Genomic features are used as biomarkers of sensitivity to kinase inhibitors used widely to treat human cancer, but effective patient stratification based on these principles remains limited in impact. Insofar as kinase inhibitors interfere with signaling dynamics, and, in turn, signaling dynamics affects inhibitor responses, we investigated associations in this study between cell-specific dynamic signaling pathways and drug sensitivity. Specifically, we measured 14 phosphoproteins under 43 different perturbed conditions (combinations of 5 stimuli and 7 inhibitors) in 14 colorectal cancer cell lines, building cell line-specific dynamic logic models of underlying signaling networks.

Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A.

Despite the approval of numerous molecular targeted drugs, long-term antiproliferative efficacy is rarely achieved and therapy resistance remains a central obstacle of cancer care. Combined inhibition of multiple cancer-driving pathways promises to improve antiproliferative efficacy. HIF-1 is a driver of gastric cancer and considered to be an attractive target for therapy.

Hypoxia-induced gene expression results from selective mRNA partitioning to the endoplasmic reticulum.

Protein synthesis is a primary energy-consuming process in the cell. Therefore, under hypoxic conditions, rapid inhibition of global mRNA translation represents a major protective strategy to maintain energy metabolism. How some mRNAs, especially those that encode crucial survival factors, continue to be efficiently translated in hypoxia is not completely understood.

Consequences of feedback in signal transduction for targeted therapies.

Over the last two decades, many small-molecule inhibitors that target kinase signalling have been developed. More than 20 of these inhibitors are FDA (U.S.

Network quantification of EGFR signaling unveils potential for targeted combination therapy.

The epidermal growth factor receptor (EGFR) signaling network is activated in most solid tumors, and small-molecule drugs targeting this network are increasingly available. However, often only specific combinations of inhibitors are effective. Therefore, the prediction of potent combinatorial treatments is a major challenge in targeted cancer therapy.