TENSION SIGNED
Targeting replication stress recovery pathways in oncology
Total Cost €
0EC-Contrib. €
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0TENSION project word cloud
Explore the words cloud of the TENSION project. It provides you a very rough idea of what is the project "TENSION" about.
Project "TENSION" data sheet
The following table provides information about the project.
| Coordinator |
ACADEMISCH ZIEKENHUIS GRONINGEN
Organization address contact info |
| Coordinator Country | Netherlands [NL] |
| Total cost | 1˙972˙500 € |
| EC max contribution | 1˙972˙500 € (100%) |
| Programme |
1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC)) |
| Code Call | ERC-2015-CoG |
| Funding Scheme | ERC-COG |
| Starting year | 2016 |
| Duration (year-month-day) | from 2016-08-01 to 2021-07-31 |
Partnership
Take a look of project's partnership.
| # | ||||
|---|---|---|---|---|
| 1 | ACADEMISCH ZIEKENHUIS GRONINGEN | NL (GRONINGEN) | coordinator | 1˙972˙500.00 |
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Project objective
Genomic instability characterizes tumors, which have no clear ‘oncogenic-driver’ mutation, including triple-negative breast cancers (TNBCs). These patients do not benefit from molecularly targeted treatment and urgently need better treatment options. Increasing evidence points to replication stress as the driver of genomic instability. Since replication stress compromises cell viability, cells have evolved mechanisms to mitigate this threat. Recently, I discovered a novel cellular mechanism—mitotic Replication Stress Recovery (RSR)—that acts as an ‘emergency brake’ during mitosis, allowing recovery from high levels of replication stress. This machinery is critical for tumor cell survival, and therefore constitutes a promising target for anti-cancer drug development. However, it is unclear how this mitotic RSR is organized molecularly and how it can be targeted therapeutically.
In this project, I aim to molecularly define and therapeutically target the Mitotic Replication Stress Recovery (RSR) machinery in triple-negative breast cancer cells.
To this end, I will implement a series of complementary innovative strategies. First, I will use mass-spec-based proteomics to molecularly characterize components and wiring of the mitotic RSR machinery. Second, to identify the genetic profiles of cancer subgroups that are sensitive to inactivation of the mitotic RSR, functional genetic screens will be combined with visualization and quantification of replication stress in genomically-defined human cancer samples. Finally, my findings will be translated to the pre-clinical situation by exploring the feasibility of therapeutic inactivation of the RSR machinery in vitro and in vivo in a panel of triple-negative breast cancer models.
In summary, TENSION will provide advanced insight into the composition and wiring of the mitotic RSR machinery and will reveal the potency of targeting this pathway therapeutically for TNBCs and other hard-to-treat, genomically instable cancers.
Publications
| year | authors and title | journal | last update |
|---|---|---|---|
| 2019 |
Anne Margriet Heijink, Marieke Everts, Megan E. Honeywell, Ryan Richards, Yannick P. Kok, Elisabeth G.E. de Vries, Michael J. Lee, Marcel A.T.M. van Vugt Modeling of Cisplatin-Induced Signaling Dynamics in Triple-Negative Breast Cancer Cells Reveals Mediators of Sensitivity published pages: 2345-2357.e5, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2019.07.070 |
Cell Reports 28/9 | 2019-10-04 |
| 2019 |
Francien Talens, Marcel A.T.M. Van Vugt Inflammatory signaling in genomically instable cancers published pages: 1830-1848, ISSN: 1538-4101, DOI: 10.1080/15384101.2019.1638192 |
Cell Cycle 18/16 | 2019-10-04 |
| 2019 |
Chirantani Mukherjee, Vivek Tripathi, Eleni Maria Manolika, Anne Margriet Heijink, Giulia Ricci, Sarra Merzouk, H. Rudolf de Boer, Jeroen Demmers, Marcel A. T. M. van Vugt, Arnab Ray Chaudhuri RIF1 promotes replication fork protection and efficient restart to maintain genome stability published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-019-11246-1 |
Nature Communications 10/1 | 2019-10-04 |
| 2017 |
Francien Talens, Mathilde Jalving, Jourik A. Gietema, Marcel A. Van Vugt Therapeutic targeting and patient selection for cancers with homologous recombination defects published pages: 565-581, ISSN: 1746-0441, DOI: 10.1080/17460441.2017.1322061 |
Expert Opinion on Drug Discovery 12/6 | 2019-05-27 |
| 2019 |
Anne Margriet Heijink, Francien Talens, Lucas T. Jae, Stephanie E. van Gijn, Rudolf S. N. Fehrmann, Thijn R. Brummelkamp, Marcel A. T. M. van Vugt BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-018-07927-y |
Nature Communications 10/1 | 2019-05-10 |
| 2017 |
Pepijn M. Schoonen, Marcel A.T.M. van Vugt Never tear us a-PARP: Dealing with DNA lesions during mitosis published pages: e1382670, ISSN: 2372-3556, DOI: 10.1080/23723556.2017.1382670 |
Molecular & Cellular Oncology 5/1 | 2019-05-10 |
| 2018 |
Mathilde R. W. de Jong, Lydia Visser, Gerwin Huls, Arjan Diepstra, Marcel van Vugt, Emanuele Ammatuna, Rozemarijn S. van Rijn, Edo Vellenga, Anke van den Berg, Rudolf S. N. Fehrmann, Tom van Meerten Identification of relevant drugable targets in diffuse large B-cell lymphoma using a genome-wide unbiased CD20 guilt-by association approach published pages: e0193098, ISSN: 1932-6203, DOI: 10.1371/journal.pone.0193098 |
PLOS ONE 13/2 | 2019-05-10 |
| 2018 |
Ewa Gogola, Alexandra A. Duarte, Julian R. de Ruiter, Wouter W. Wiegant, Jonas A. Schmid, Roebi de Bruijn, Dominic I. James, Sergi Guerrero Llobet, Daniel J. Vis, Stefano Annunziato, Bram van den Broek, Marco Barazas, Ariena Kersbergen, Marieke van de Ven, Madalena Tarsounas, Donald J. Ogilvie, Marcel van Vugt, Lodewyk F.A. Wessels, Jirina Bartkova, Irina Gromova, Miguel Andújar-Sánchez, Jiri Bartek, Massimo Lopes, Haico van Attikum, Piet Borst, Jos Jonkers, Sven Rottenberg Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality published pages: 1078-1093.e12, ISSN: 1535-6108, DOI: 10.1016/j.ccell.2018.05.008 |
Cancer Cell 33/6 | 2019-05-10 |
| 2019 |
Stephanie E. van Gijn, Elles Wierenga, Nathalie van den Tempel, Yannick P. Kok, Anne Margriet Heijink, Diana C. J. Spierings, Floris Foijer, Marcel A. T. M. van Vugt, Rudolf S. N. Fehrmann TPX2/Aurora kinase A signaling as a potential therapeutic target in genomically unstable cancer cells published pages: 852-867, ISSN: 0950-9232, DOI: 10.1038/s41388-018-0470-2 |
Oncogene 38/6 | 2019-05-10 |
| 2018 |
Walderik W. Zomerman, Sabine L.A. Plasschaert, Siobhan Conroy, Frank J. Scherpen, Tiny G.J. Meeuwsen-de Boer, Harm J. Lourens, Sergi Guerrero Llobet, Marlinde J. Smit, Lorian Slagter-Menkema, Annika Seitz, Corrie E.M. Gidding, Esther Hulleman, Pieter Wesseling, Lisethe Meijer, Leon C. van Kempen, Anke van den Berg, Daniël O. Warmerdam, Frank A.E. Kruyt, Floris Foijer, Marcel A.T.M. van Vugt, Wilfred F.A. den Dunnen, Eelco W. Hoving, Victor Guryev, Eveline S.J.M. de Bont, Sophia W.M. Bruggeman Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma published pages: 3206-3216, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2018.02.089 |
Cell Reports 22/12 | 2019-05-10 |
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