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| 2. |
- Abenius, Tobias, 1979, et al.
(författare)
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System-scale network modeling of cancer using EPoC
- 2012
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Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer New York. - 0065-2598. - 9781441972095 ; 736:5, s. 617-643
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Tidskriftsartikel (refereegranskat)abstract
- One of the central problems of cancer systems biology is to understand the complex molecular changes of cancerous cells and tissues, and use this understanding to support the development of new targeted therapies. EPoC (Endogenous Perturbation analysis of Cancer) is a network modeling technique for tumor molecular profiles. EPoC models are constructed from combined copy number aberration (CNA) and mRNA data and aim to (1) identify genes whose copy number aberrations significantly affect target mRNA expression and (2) generate markers for long- and short-term survival of cancer patients. Models are constructed by a combination of regression and bootstrapping methods. Prognostic scores are obtained from a singular value decomposition of the networks. We have previously analyzed the performance of EPoC using glioblastoma data from The Cancer Genome Atlas (TCGA) consortium, and have shown that resulting network models contain both known and candidate disease-relevant genes as network hubs, as well as uncover predictors of patient survival. Here, we give a practical guide how to perform EPoC modeling in practice using R, and present a set of alternative modeling frameworks.
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| 4. |
- Castell, Alina, et al.
(författare)
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MYCMI-7 : A Small MYC-Binding Compound that Inhibits MYC: MAX Interaction and Tumor Growth in a MYC-Dependent Manner
- 2022
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Ingår i: Cancer Research Communications. - : American Association For Cancer Research (AACR). - 2767-9764. ; 2:3, s. 182-201
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Tidskriftsartikel (refereegranskat)abstract
- Deregulated expression of MYC family oncogenes occurs frequently in human cancer and is often associated with aggressive disease and poor prognosis. While MYC is a highly warranted target, it has been considered "undruggable," and no specific anti-MYC drugs are available in the clinic. We recently identified molecules named MYCMIs that inhibit the interaction between MYC and its essential partner MAX. Here we show that one of these molecules, MYCMI-7, efficiently and selectively inhibits MYC:MAX and MYCN:MAX interactions in cells, binds directly to recombinant MYC, and reduces MYC-driven transcription. In addition, MYCMI-7 induces degradation of MYC and MYCN proteins. MYCMI-7 potently induces growth arrest/apoptosis in tumor cells in a MYC/MYCN-dependent manner and downregulates the MYC pathway on a global level as determined by RNA sequencing. Sensitivity to MYCMI-7 correlates with MYC expression in a panel of 60 tumor cell lines and MYCMI-7 shows high efficacy toward a collection of patient-derived primary glioblastoma and acute myeloid leukemia (AML) ex vivo cultures. Importantly, a variety of normal cells be- come G1 arrested without signs of apoptosis upon MYCMI-7 treatment. Finally, in mouse tumor models of MYC-driven AML, breast cancer, and MYCN-amplified neuroblastoma, treatment with MYCMI-7 downregu- lates MYC/MYCN, inhibits tumor growth, and prolongs survival through apoptosis with few side effects. In conclusion, MYCMI-7 is a potent and selective MYC inhibitor that is highly relevant for the development into clinically useful drugs for the treatment of MYC-driven cancer.Significance: Our findings demonstrate that the small-molecule MYCMI-7 binds MYC and inhibits interaction between MYC and MAX, thereby ham- pering MYC-driven tumor cell growth in culture and in vivo while sparing normal cells.
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| 5. |
- Claesson, Elin, 1989, et al.
(författare)
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The primary structural photoresponse of phytochrome proteins captured by a femtosecond X-ray laser
- 2020
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Ingår i: eLife. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Phytochrome proteins control the growth, reproduction, and photosynthesis of plants, fungi, and bacteria. Light is detected by a bilin cofactor, but it remains elusive how this leads to activation of the protein through structural changes. We present serial femtosecond X-ray crystallographic data of the chromophore-binding domains of a bacterial phytochrome at delay times of 1 ps and 10 ps after photoexcitation. The data reveal a twist of the D-ring, which leads to partial detachment of the chromophore from the protein. Unexpectedly, the conserved so-called pyrrole water is photodissociated from the chromophore, concomitant with movement of the A-ring and a key signaling aspartate. The changes are wired together by ultrafast backbone and water movements around the chromophore, channeling them into signal transduction towards the output domains. We suggest that the observed collective changes are important for the phytochrome photoresponse, explaining the earliest steps of how plants, fungi and bacteria sense red light.
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| 6. |
- Gerlee, Philip, 1980, et al.
(författare)
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Searching for Synergies: Matrix Algebraic Approaches for Efficient Pair Screening
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- Functionally interacting perturbations, such as synergistic drugs pairs or synthetic lethal gene pairs, are of key interest in both pharmacology and functional genomics. However, to find such pairs by traditional screening methods is both time consuming and costly. We present a novel computational-experimental framework for efficient identification of synergistic target pairs, applicable for screening of systems with sizes on the order of current drug, small RNA or SGA (Synthetic Genetic Array) libraries (>1000 targets). This framework exploits the fact that the response of a drug pair in a given system, or a pair of genes' propensity to interact functionally, can be partly predicted by computational means from (i) a small set of experimentally determined target pairs, and (ii) pre-existing data (e.g. gene ontology, PPI) on the similarities between targets. Predictions are obtained by a novel matrix algebraic technique, based on cyclical projections onto convex sets. We demonstrate the efficiency of the proposed method using drug-drug interaction data from seven cancer cell lines and gene-gene interaction data from yeast SGA screens. Our protocol increases the rate of synergism discovery significantly over traditional screening, by up to 7-fold. Our method is easy to implement and could be applied to accelerate pair screening for both animal and microbial systems.
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| 7. |
- Hansson, Caroline, 1981, et al.
(författare)
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Influence of ghrelin on the central serotonergic signaling system in mice
- 2014
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Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908. ; 79, s. 498-505
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Tidskriftsartikel (refereegranskat)abstract
- The central ghrelin signaling system engages key pathways of importance for feeding control, recently shown to include those engaged in anxiety-like behavior in rodents. Here we sought to determine whether ghrelin impacts on the central serotonin system, which has an important role in anxiety. We focused on two brain areas, the amygdala (of importance for the mediation of fear and anxiety) and the dorsal raphe (i.e. the site of origin of major afferent serotonin pathways, including those that project to the amygdala). In these brain areas, we measured serotonergic turnover (using HPLC) and the mRNA expression of a number of serotonin-related genes (using real-time PCR). We found that acute central administration of ghrelin to mice increased the serotonergic turnover in the amygdala. It also increased the mRNA expression of a number of serotonin receptors, both in the amygdala and in the dorsal raphe. Studies in ghrelin receptor (GHS-R1A) knock-out mice showed a decreased mRNA expression of serotonergic receptors in both the amygdala and the dorsal raphe, relative to their wild-type littermates. We conclude that the central serotonin system is a target for ghrelin, providing a candidate neurochemical substrate of importance for ghrelin's effects on mood. © 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
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| 9. |
- Johansson, Patrik, et al.
(författare)
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A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma
- 2020
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 32:2
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells, We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.
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