Kulic I.,Genome science Center |
Kulic I.,University of British Columbia |
Robertson G.,Genome science Center |
Chang L.,Genome science Center |
And 17 more authors.
Journal of Experimental Medicine | Year: 2015
Aberrant Notch activity is oncogenic in several malignancies, but it is unclear how expression or function of downstream elements in the Notch pathway affects tumor growth. Transcriptional regulation by Notch is dependent on interaction with the DNA-binding transcriptional repressor, RBPJ, and consequent derepression or activation of associated gene promoters. We show here that RBPJ is frequently depleted in human tumors. Depletion of RBPJ in human cancer cell lines xenografted into immunodeficient mice resulted in activation of canonical Notch target genes, and accelerated tumor growth secondary to reduced cell death. Global analysis of activated regions of the genome, as defined by differential acetylation of histone H4 (H4ac), revealed that the cell death pathway was significantly dysregulated in RBPJdepleted tumors. Analysis of transcription factor binding data identified several transcriptional activators that bind promoters with differential H4ac in RBPJ-depleted cells. Functional studies demonstrated that NF-κB and MYC were essential for survival of RBPJdepleted cells. Thus, loss of RBPJ derepresses target gene promoters, allowing Notchindependent activation by alternate transcription factors that promote tumorigenesis. © 2015 Kulic et al.
de Reuille P.B.,University of Bern |
Routier-Kierzkowska A.-L.,Max Planck Institute for Plant Breeding Research |
Kierzkowski D.,Max Planck Institute for Plant Breeding Research |
Bassel G.W.,University of Birmingham |
And 28 more authors.
eLife | Year: 2015
Morphogenesis emerges from complex multiscale interactions between genetic and mechanical processes. To understand these processes, the evolution of cell shape, proliferation and gene expression must be quantified. This quantification is usually performed either in full 3D, which is computationally expensive and technically challenging, or on 2D planar projections, which introduces geometrical artifacts on highly curved organs. Here we present MorphoGraphX (www.MorphoGraphX.org), a software that bridges this gap by working directly with curved surface images extracted from 3D data. In addition to traditional 3D image analysis, we have developed algorithms to operate on curved surfaces, such as cell segmentation, lineage tracking and fluorescence signal quantification. The software’s modular design makes it easy to include existing libraries, or to implement new algorithms. Cell geometries extracted with MorphoGraphX can be exported and used as templates for simulation models, providing a powerful platform to investigate the interactions between shape, genes and growth. © Barbier de Reuille et al.
Schmid C.A.,Institute of Molecular Cancer Research |
Robinson M.D.,Institute of Molecular Life science |
Robinson M.D.,Swiss Institute of Bioinformatics |
Scheifinger N.A.,Institute of Molecular Cancer Research |
And 5 more authors.
Journal of Experimental Medicine | Year: 2015
The epigenetic dysregulation of tumor suppressor genes is an important driver of human carcinogenesis. We have combined genome-wide DNA methylation analyses and gene expression profiling after pharmacological DNA demethylation with functional screening to identify novel tumor suppressors in diffuse large B cell lymphoma (DLBCL). We find that a CpG island in the promoter of the dual-specificity phosphatase DUSP4 is aberrantly methylated in nodal and extranodal DLBCL, irrespective of ABC or GCB subtype, resulting in loss of DUSP4 expression in 75% of >200 examined cases. The DUSP4 genomic locus is further deleted in up to 13% of aggressive B cell lymphomas, and the lack of DUSP4 is a negative prognostic factor in three independent cohorts of DLBCL patients. Ectopic expression of wild-type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. Pharmacological or dominantnegative JNK inhibition restricts DLBCL survival in vitro and in vivo and synergizes strongly with the Bruton's tyrosine kinase inhibitor ibrutinib. Our results indicate that DLBCL cells depend on JNK signaling for survival. This finding provides a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, ideally in synthetic lethal combinations with inhibitors of chronic active B cell receptor signaling. © 2015 Schmid et al.
Flori M.,University of Zürich |
Schmid C.A.,University of Zürich |
Sumrall E.T.,University of Zürich |
Tzankov A.,University of Basel |
And 5 more authors.
Blood | Year: 2016
Aberrant expression of the oncogenic transcription factor forkhead boxprotein 1 (FOXP1) is a common feature of diffuse large B-cell lymphoma (DLBCL). We have combined chromatin immunoprecipitation and gene expression profiling after FOXP1 depletion with functional screening to identify targets of FOXP1 contributing to tumor cell survival. We find that the sphingosine-1-phosphate receptor 2 (S1PR2) is repressed by FOXP1 in activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL cell lines with aberrantly high FOXP1 levels; S1PR2 expression is further inversely correlated with FOXP1 expression in 3 patient cohorts. Ectopic expression of wild-type S1PR2, but not a point mutant incapable of activating downstream signaling pathways, induces apoptosis in DLBCL cells and restricts tumor growth in subcutaneous and orthotopic models of the disease. The proapoptotic effects of S1PR2 are phenocopied by ectopic expression of the small G protein Ga13 but are independent of AKT signaling. We further show that low S1PR2 expression is a strong negative prognosticator of patient survival, alone and especially in combination with high FOXP1 expression. The S1PR2 locus has previously been demonstrated to be recurrently mutated in GCB DLBCL; the transcriptional silencing of S1PR2 by FOXP1 represents an alternative mechanism leading to inactivation of this important hematopoietic tumor suppressor. © 2016 by The American Society of Hematology.
Port F.,Institute of Molecular Life science |
Basler K.,Institute of Molecular Life science
Traffic | Year: 2010
Proteins of the Wnt family are secreted signaling molecules that regulate multiple processes in animal development and control tissue homeostasis in the adult. Wnts spread over considerable distances to regulate gene expression in cells located at distant sites. Paradoxically, Wnts are poorly mobile because of their posttranslational modification with lipids. Recent evidence suggests that several pathways exist that are capable of transforming hydrophobic, insoluble Wnts into long-range signaling molecules. Furthermore, the discovery of Wntless as a protein specifically required for the secretion of Wnt suggests that Wnt trafficking through the secretory pathway is already under special scrutiny. Here, we review recent data on the molecular machinery that controls Wnt secretion and discuss how Wnts can be mobilized for long-range signaling. © 2010 John Wiley & Sons A/S.
PubMed | Institute of Molecular Life science
Type: Journal Article | Journal: Developmental cell | Year: 2011
We use the Dpp morphogen gradient in the Drosophila wing disc as a model to address the fundamental question of how a gradient of a growth factor can produce uniform growth. We first show that proper expression and subcellular localization of components in the Fat tumor-suppressor pathway, which have been argued to depend on Dpp activity differences, are not reliant on the Dpp gradient. We next analyzed cell proliferation in discs with uniformly high Dpp or uniformly low Fat signaling activity and found that these pathways regulate growth ina complementary manner. While the Dpp mediator Brinker inhibits growth in the primordium primarily in the lateral regions, Fat represses growth mostly in the medial region. Together, our results indicate that the activities of both signaling pathways are regulated in a parallel rather than sequential manner and that uniform proliferation is achieved by their complementary action on growth.
Schwank G.,Institute of Molecular Life science |
Tauriello G.,ETH Zurich |
Yagi R.,Institute of Molecular Life science |
Kranz E.,Institute of Molecular Life science |
And 2 more authors.
Developmental Cell | Year: 2011
We use the Dpp morphogen gradient in the Drosophila wing disc as a model to address the fundamental question of how a gradient of a growth factor can produce uniform growth. We first show that proper expression and subcellular localization of components in the Fat tumor-suppressor pathway, which have been argued to depend on Dpp activity differences, are not reliant on the Dpp gradient. We next analyzed cell proliferation in discs with uniformly high Dpp or uniformly low Fat signaling activity and found that these pathways regulate growth in a complementary manner. While the Dpp mediator Brinker inhibits growth in the primordium primarily in the lateral regions, Fat represses growth mostly in the medial region. Together, our results indicate that the activities of both signaling pathways are regulated in a parallel rather than sequential manner and that uniform proliferation is achieved by their complementary action on growth. © 2011 Elsevier Inc.