Swiss Institute for Experimental Cancer Research ISREC

Lausanne, Switzerland

Swiss Institute for Experimental Cancer Research ISREC

Lausanne, Switzerland
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Schmittnaegel M.,Swiss Institute for Experimental Cancer Research ISREC | Rigamonti N.,Swiss Institute for Experimental Cancer Research ISREC | Rigamonti N.,Molecular Partners | Kadioglu E.,Swiss Institute for Experimental Cancer Research ISREC | And 8 more authors.
Science Translational Medicine | Year: 2017

Pathological angiogenesis is a hallmark of cancer and a therapeutic target. Vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2; also known as ANG2) are proangiogenic cytokines that sustain tumor angiogenesis and limit antitumor immunity. We show that combined ANGPT2 and VEGFA blockade by a bispecific antibody (A2V) provided superior therapeutic benefits, as compared to the single agents, in both genetically engineered and transplant tumor models, including metastatic breast cancer (MMTV-PyMT), pancreatic neuroendocrine tumor (RIP1-Tag2), and melanoma. Mechanistically, A2V promoted vascular regression, tumor necrosis, and antigen presentation by intratumoral phagocytes. A2V also normalized the remaining blood vessels and facilitated the extravasation and perivascular accumulation of activated, interferon-g (IFNg)-expressing CD8+ cytotoxic T lymphocytes (CTLs). Whereas the antitumoral activity of A2V was, at least partly, CTL-dependent, perivascular T cells concurrently up-regulated the expression of the immune checkpoint ligand programmed cell death ligand 1 (PD-L1) in tumor endothelial cells. IFNg neutralization blunted this adaptive response, and PD-1 blockade improved tumor control by A2V in different cancer models. These findings position immune cells as key effectors of antiangiogenic therapy and support the rationale for cotargeting angiogenesis and immune checkpoints in cancer therapy. © 2017 The Authors, some rights reserved.


Baranek S.,Ecole Polytechnique Federale de Lausanne | Bezler A.,Swiss Institute for Experimental Cancer Research ISREC | Adamczyk C.,Ecole Polytechnique Federale de Lausanne | Gonczy P.,Swiss Institute for Experimental Cancer Research ISREC | Renaud P.,Ecole Polytechnique Federale de Lausanne
14th International Conference on Miniaturized Systems for Chemistry and Life Sciences 2010, MicroTAS 2010 | Year: 2010

This paper reports on a new microfluidic device for temperature stimulation of cell in in-vitro culture. Micro-electrodes in a meander shape are embedded into the microfluidic channels to generate either a temperature gradient through the culture chamber or a local heat spot under specific cells. One promising application is the control of cell division rate. Here we present first results of the synchronization of cell division in a two-cell stage embryos of C. Elegans.


Valenta T.,University of Zürich | Gay M.,University of Zürich | Steiner S.,University of Zürich | Draganova K.,University of Zürich | And 6 more authors.
Genes and Development | Year: 2011

β-Catenin, apart from playing a cell-adhesive role, is a key nuclear effector of Wnt signaling. Based on activity assays in Drosophila, we generated mouse strains where the endogenous β-catenin protein is replaced by mutant forms, which retain the cell adhesion function but lack either or both of the N- and the C-terminal transcriptional outputs. The C-terminal activity is essential for mesoderm formation and proper gastrulation, whereas N-terminal outputs are required later during embryonic development. By combining the double-mutant β-catenin with a conditional null allele and a Wnt1-Cre driver, we probed the role of Wnt/β-catenin signaling in dorsal neural tube development. While loss of β-catenin protein in the neural tube results in severe cell adhesion defects, the morphology of cells and tissues expressing the double-mutant form is normal. Surprisingly, Wnt/β-catenin signaling activity only moderately regulates cell proliferation, but is crucial for maintaining neural progenitor identity and for neuronal differentiation in the dorsal spinal cord. Our model animals thus allow dissecting signaling and structural functions of β-catenin in vivo and provide the first genetic tool to generate cells and tissues that entirely and exclusively lack canonical Wnt pathway activity. © 2011 by Cold Spring Harbor Laboratory Press.


Sarode B.,Ecole Polytechnique Federale de Lausanne | Sarode B.,Swiss Institute for Experimental Cancer Research ISREC | Nowell C.S.,Ecole Polytechnique Federale de Lausanne | Nowell C.S.,Swiss Institute for Experimental Cancer Research ISREC | And 11 more authors.
Pigment Cell and Melanoma Research | Year: 2014

Summary: The ciliary body and iris are pigmented epithelial structures in the anterior eye segment that function to maintain correct intra-ocular pressure and regulate exposure of the internal eye structures to light, respectively. The cellular and molecular factors that mediate the development of the ciliary body and iris from the ocular pigmented epithelium remain to be fully elucidated. Here, we have investigated the role of Notch signaling during the development of the anterior pigmented epithelium by using genetic loss- and gain-of-function approaches. Loss of canonical Notch signaling results in normal iris development but absence of the ciliary body. This causes progressive hypotony and over time leads to phthisis bulbi, a condition characterized by shrinkage of the eye and loss of structure/function. Conversely, Notch gain-of-function results in aniridia and profound ciliary body hyperplasia, which causes ocular hypertension and glaucoma-like disease. Collectively, these data indicate that Notch signaling promotes ciliary body development at the expense of iris formation and reveals novel animal models of human ocular pathologies. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Chen L.Y.,Swiss Institute for Experimental Cancer Research ISREC
Nucleus (Austin, Tex.) | Year: 2013

Telomeric DNA at eukaryotic chromosome ends terminates with single stranded 3' G-rich overhangs. The overhang is generated by the interplay of several dynamic processes including semiconservative DNA replication, 3' end elongation by telomerase, C-strand fill-in synthesis and nucleolytic processing. The mammalian CST (CTC1-STN1-TEN1) complex is directly involved at several stages of telomere end formation. Elucidation of its structural organization and identification of interaction partners support the notion that mammalian CST is, as its yeast counterpart, a RPA-like complex. CST binding at mammalian telomere 3' overhangs increases upon their elongation by telomerase. Formation of a trimeric CST complex at telomeric 3'overhangs leads to telomerase inhibition and at the same time mediates a physical interaction with DNA polymerase-α. Thus CST seems to play critical roles in coordinating telomerase elongation and fill-in synthesis to complete telomere replication.


David F.P.A.,Ecole Polytechnique Federale de Lausanne | David F.P.A.,Swiss Institute of Bioinformatics | Delafontaine J.,Ecole Polytechnique Federale de Lausanne | Delafontaine J.,Swiss Institute of Bioinformatics | And 20 more authors.
PLoS ONE | Year: 2014

The HTSstation analysis portal is a suite of simple web forms coupled to modular analysis pipelines for various applications of High-Throughput Sequencing including ChIP-seq, RNA-seq, 4C-seq and re-sequencing. HTSstation offers biologists the possibility to rapidly investigate their HTS data using an intuitive web application with heuristically pre-defined parameters. A number of open-source software components have been implemented and can be used to build, configure and run HTS analysis pipelines reactively. Besides, our programming framework empowers developers with the possibility to design their own workflows and integrate additional third-party software. The HTSstation web application is accessible at http://htsstation.epfl.ch. © 2014 David et al.


Chen L.-Y.,Swiss Institute for Experimental Cancer Research ISREC | Lingner J.,Swiss Institute for Experimental Cancer Research ISREC
Nucleus (United States) | Year: 2013

Telomeric DNA at eukaryotic chromosome ends terminates with single stranded 3' G-rich overhangs. The overhang is generated by the interplay of several dynamic processes including semiconservative DNA replication, 3' end elongation by telomerase, C-strand fill-in synthesis and nucleolytic processing. The mammalian CST (CTC1-STN1-TEN1) complex is directly involved at several stages of telomere end formation. Elucidation of its structural organization and identification of interaction partners support the notion that mammalian CST is, as its yeast counterpart, a RPA-like complex. CST binding at mammalian telomere 3' overhangs increases upon their elongation by telomerase. Formation of a trimeric CST complex at telomeric 3' overhangs leads to telomerase inhibition and at the same time mediates a physical interaction with DNA polymerase-α. Thus CST seems to play critical roles in coordinating telomerase elongation and fill-in synthesis to complete telomere replication. © 2013 Landes Bioscience.


PubMed | Swiss Institute for Experimental Cancer Research ISREC
Type: Journal Article | Journal: Journal of cell science | Year: 2011

The yeast nuclear scaffold has been shown to bind with high affinity to genomic sequences that permit autonomous DNA replication of plasmids (ARS elements). We describe here conditions for the isolation of a histone-free nuclear substructure, the nuclear scaffold, from Saccharomyces cerevisiae. We examine the protein composition of this structure,and the conditions under which topoisomerase II, the nuclear factor RAP-1 and RNA polymerase II co-fractionate with the scaffold. We find that exposure of nuclei to a combined metal and heat treatment (0.5mM Cu(2) +, 37 degree centigrade prior to detergent extraction is required for effective stabilization of these proteins with the scaffold. Electron microscopy of the residual nuclei extracted with non-ionic detergents shows the absence of a typical peripheral lamina structure.


PubMed | SWISS INSTITUTE FOR EXPERIMENTAL CANCER RESEARCH ISREC
Type: Comment | Journal: Blood | Year: 2015

In this issue of Blood, Appelmann et al provide evidence for prolonged survival and prevention of resistance in a mouse model of Philadelphia chromosomepositive (Ph+) acute lymphoblastic leukemia (ALL) by combined targeting of the BCR-ABL kinase and Janus kinase 2 (JAK2) with dasatinib and ruxolitinib, respectively.

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