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  1. Article ; Online: Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens

    Inês A. M. Barbosa / Rajaraman Gopalakrishnan / Samuele Mercan / Thanos P. Mourikis / Typhaine Martin / Simon Wengert / Caibin Sheng / Fei Ji / Rui Lopes / Judith Knehr / Marc Altorfer / Alicia Lindeman / Carsten Russ / Ulrike Naumann / Javad Golji / Kathleen Sprouffske / Louise Barys / Luca Tordella / Dirk Schübeler /
    Tobias Schmelzle / Giorgio G. Galli

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 15

    Abstract: Abstract YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo ... ...

    Abstract Abstract YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, in Uveal Melanoma (UM), YAP is activated in a Hippo-independent manner. To date, it is unclear if and how the different oncogenic lesions activating YAP impact its oncogenic program, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, despite YAP being essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. Systematic functional interrogation of YAP regulatory elements in both cancer types reveals convergent regulation of broad oncogenic drivers in both MPM and UM, but also strikingly selective programs. Our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types.
    Keywords Science ; Q
    Language English
    Publishing date 2023-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Dissection of the interaction between the intrinsically disordered YAP protein and the transcription factor TEAD

    Yannick Mesrouze / Fedir Bokhovchuk / Marco Meyerhofer / Patrizia Fontana / Catherine Zimmermann / Typhaine Martin / Clara Delaunay / Dirk Erdmann / Tobias Schmelzle / Patrick Chène

    eLife, Vol

    2017  Volume 6

    Abstract: TEAD (TEA/ATTS domain) transcription factors are the most distal effectors of the Hippo pathway. YAP (Yes-associated protein) is a coactivator protein which, upon binding to TEAD proteins, stimulates their transcriptional activity. Since the Hippo ... ...

    Abstract TEAD (TEA/ATTS domain) transcription factors are the most distal effectors of the Hippo pathway. YAP (Yes-associated protein) is a coactivator protein which, upon binding to TEAD proteins, stimulates their transcriptional activity. Since the Hippo pathway is deregulated in various cancers, designing inhibitors of the YAP:TEAD interaction is an attractive therapeutic strategy for oncology. Understanding the molecular events that take place at the YAP:TEAD interface is therefore important not only to devise drug discovery approaches, but also to gain knowledge on TEAD regulation. In this report, combining single site-directed mutagenesis and double mutant analyses, we conduct a detailed analysis on the role of several residues located at the YAP:TEAD interface. Our results provide quantitative understanding of the interactions taking place at the YAP:TEAD interface and give insights into the formation of the YAP:TEAD complex and more particularly on the interaction between TEAD and the Ω-loop found in YAP.
    Keywords protein-protein interaction ; intrinsically disordered protein ; molecular recognitiom ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2017-04-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Correction of copy number induced false positives in CRISPR screens.

    Antoine de Weck / Javad Golji / Michael D Jones / Joshua M Korn / Eric Billy / E Robert McDonald / Tobias Schmelzle / Hans Bitter / Audrey Kauffmann

    PLoS Computational Biology, Vol 14, Iss 7, p e

    2018  Volume 1006279

    Abstract: Cell autonomous cancer dependencies are now routinely identified using CRISPR loss-of-function viability screens. However, a bias exists that makes it difficult to assess the true essentiality of genes located in amplicons, since the entire amplified ... ...

    Abstract Cell autonomous cancer dependencies are now routinely identified using CRISPR loss-of-function viability screens. However, a bias exists that makes it difficult to assess the true essentiality of genes located in amplicons, since the entire amplified region can exhibit lethal scores. These false-positive hits can either be discarded from further analysis, which in cancer models can represent a significant number of hits, or methods can be developed to rescue the true-positives within amplified regions. We propose two methods to rescue true positive hits in amplified regions by correcting for this copy number artefact. The Local Drop Out (LDO) method uses the relative lethality scores within genomic regions to assess true essentiality and does not require additional orthogonal data (e.g. copy number value). LDO is meant to be used in screens covering a dense region of the genome (e.g. a whole chromosome or the whole genome). The General Additive Model (GAM) method models the screening data as a function of the known copy number values and removes the systematic effect from the measured lethality. GAM does not require the same density as LDO, but does require prior knowledge of the copy number values. Both methods have been developed with single sample experiments in mind so that the correction can be applied even in smaller screens. Here we demonstrate the efficacy of both methods at removing the copy number effect and rescuing hits from some of the amplified regions. We estimate a 70-80% decrease of false positive hits with either method in regions of high copy number compared to no correction.
    Keywords Biology (General) ; QH301-705.5
    Subject code 310
    Language English
    Publishing date 2018-07-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: PAX8 and MECOM are interaction partners driving ovarian cancer

    Melusine Bleu / Fanny Mermet-Meillon / Verena Apfel / Louise Barys / Laura Holzer / Marianne Bachmann Salvy / Rui Lopes / Inês Amorim Monteiro Barbosa / Cecile Delmas / Alexandra Hinniger / Suzanne Chau / Markus Kaufmann / Simon Haenni / Karolin Berneiser / Maria Wahle / Ivana Moravec / Alexandra Vissières / Tania Poetsch / Erik Ahrné /
    Nathalie Carte / Johannes Voshol / Elisabeth Bechter / Jacques Hamon / Marco Meyerhofer / Dirk Erdmann / Matteo Fischer / Therese Stachyra / Felix Freuler / Sascha Gutmann / César Fernández / Tobias Schmelzle / Ulrike Naumann / Guglielmo Roma / Kate Lawrenson / Cristina Nieto-Oberhuber / Amanda Cobos-Correa / Stephane Ferretti / Dirk Schübeler / Giorgio Giacomo Galli

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 12

    Abstract: Lineage-restricted transcription factor PAX8 is oncogenic in ovarian cancer cells. Here the authors show that PAX8 interacts and recruits a splice variant of the MECOM locus PRDM3 to control the gene expression module involved in adhesion and ... ...

    Abstract Lineage-restricted transcription factor PAX8 is oncogenic in ovarian cancer cells. Here the authors show that PAX8 interacts and recruits a splice variant of the MECOM locus PRDM3 to control the gene expression module involved in adhesion and extracellular matrix, and consequently promotes ovarian tumorigenesis.
    Keywords Science ; Q
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article: Akt and ERK Control the Proliferative Response of Mammary Epithelial Cells to the Growth Factors IGF-1 and EGF Through the Cell Cycle Inhibitor p57Kip2

    Worster, Devin T / Bjorn Millard / Eric S. Lightcap / Gordon B. Mills / Joan S. Brugge / John G. Albeck / Nicole L. Solimini / Tobias Schmelzle

    Science signaling. 2012 Mar. 6, v. 5, no. 214

    2012  

    Abstract: Epithelial cells respond to growth factors including epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-1), and insulin. Using high-content immunofluorescence microscopy, we quantitated differences in signaling networks downstream of EGF, ... ...

    Abstract Epithelial cells respond to growth factors including epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-1), and insulin. Using high-content immunofluorescence microscopy, we quantitated differences in signaling networks downstream of EGF, which stimulated proliferation of mammary epithelial cells, and insulin or IGF-1, which enhanced the proliferative response to EGF but did not stimulate proliferation independently. We found that the abundance of the cyclin-dependent kinase inhibitors p21Cip1 and p57Kip2 increased in response to IGF-1 or insulin but decreased in response to EGF. Depletion of p57Kip2, but not p21Cip1, rendered IGF-1 or insulin sufficient to induce cellular proliferation in the absence of EGF. Signaling through the PI3K (phosphatidylinositol 3-kinase)–Akt–mTOR (mammalian target of rapamycin) pathway was necessary and sufficient for the increase in p57Kip2, whereas MEK [mitogen-activated or extracellular signal–regulated protein kinase (ERK) kinase]–ERK activity suppressed this increase, forming a regulatory circuit that limited proliferation in response to unaccompanied Akt activity. Knockdown of p57Kip2 enhanced the proliferative phenotype induced by tumor-associated PI3K mutant variants and released mammary epithelial acini from growth arrest during morphogenesis in three-dimensional culture. These results provide a potential explanation for the context-dependent proliferative activities of insulin and IGF-1 and for the finding that the CDKN1C locus encoding p57Kip2 is silenced in many breast cancers, which frequently show hyperactivation of the PI3K pathway. The status of p57Kip2 may thus be an important factor to assess when considering targeted therapy against the ERK or PI3K pathways.
    Keywords breast neoplasms ; cell cycle ; cell proliferation ; cyclin-dependent kinase ; epidermal growth factor ; epithelial cells ; epithelium ; fluorescence microscopy ; insulin ; insulin-like growth factor I ; loci ; mammals ; mammary glands ; mitogen-activated protein kinase ; morphogenesis ; mutants ; phenotype ; phosphatidylinositol 3-kinase ; rapamycin ; therapeutics
    Language English
    Dates of publication 2012-0306
    Size p. ra19.
    Publishing place AAAS
    Document type Article
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.2001986
    Database NAL-Catalogue (AGRICOLA)

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  6. Article ; Online: The tyrosine phosphatase PTPN14 is a negative regulator of YAP activity.

    Chrysiis Michaloglou / Waltraut Lehmann / Typhaine Martin / Clara Delaunay / Andreas Hueber / Louise Barys / Honglin Niu / Eric Billy / Markus Wartmann / Moriko Ito / Christopher J Wilson / Mary Ellen Digan / Andreas Bauer / Hans Voshol / Gerhard Christofori / William R Sellers / Francesco Hofmann / Tobias Schmelzle

    PLoS ONE, Vol 8, Iss 4, p e

    2013  Volume 61916

    Abstract: The Hippo (Hpo) pathway is a novel signaling pathway that controls organ size in Drosophila and mammals and is deregulated in a variety of human cancers. It consists of a set of kinases that, through a number of phosphorylation events, inactivate YAP, a ... ...

    Abstract The Hippo (Hpo) pathway is a novel signaling pathway that controls organ size in Drosophila and mammals and is deregulated in a variety of human cancers. It consists of a set of kinases that, through a number of phosphorylation events, inactivate YAP, a transcriptional co-activator that controls cellular proliferation and apoptosis. We have identified PTPN14 as a YAP-binding protein that negatively regulates YAP activity by controlling its localization. Mechanistically, we find that the interaction of ectopic YAP with PTPN14 can be mediated by the respective WW and PPxY motifs. However, the PTPN14 PPxY motif and phosphatase activity appear to be dispensable for the negative regulation of endogenous YAP, likely suggesting more complex mechanisms of interaction and modulation. Finally, we demonstrate that PTPN14 downregulation can phenocopy YAP activation in mammary epithelial cells and synergize with YAP to induce oncogenic transformation.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: K-RAS mutant pancreatic tumors show higher sensitivity to MEK than to PI3K inhibition in vivo.

    Irmgard Hofmann / Andreas Weiss / Gaelle Elain / Maria Schwaederle / Dario Sterker / Vincent Romanet / Tobias Schmelzle / Albert Lai / Saskia M Brachmann / Mohamed Bentires-Alj / Thomas M Roberts / William R Sellers / Francesco Hofmann / Sauveur-Michel Maira

    PLoS ONE, Vol 7, Iss 8, p e

    2012  Volume 44146

    Abstract: Activating K-RAS mutations occur at a frequency of 90% in pancreatic cancer, and to date no therapies exist targeting this oncogene. K-RAS signals via downstream effector pathways such as the MAPK and the PI3K signaling pathways, and much effort has been ...

    Abstract Activating K-RAS mutations occur at a frequency of 90% in pancreatic cancer, and to date no therapies exist targeting this oncogene. K-RAS signals via downstream effector pathways such as the MAPK and the PI3K signaling pathways, and much effort has been focused on developing drugs targeting components of these pathways. To better understand the requirements for K-RAS and its downstream signaling pathways MAPK and PI3K in pancreatic tumor maintenance, we established an inducible K-RAS knock down system that allowed us to ablate K-RAS in established tumors. Knock down of K-RAS resulted in impaired tumor growth in all pancreatic xenograft models tested, demonstrating that K-RAS expression is indeed required for tumor maintenance of K-RAS mutant pancreatic tumors. We further examined signaling downstream of K-RAS, and detected a robust reduction of pERK levels upon K-RAS knock down. In contrast, no effect on pAKT levels could be observed due to almost undetectable basal expression levels. To investigate the requirement of the MAPK and the PI3K pathways on tumor maintenance, three selected pancreatic xenograft models were tested for their response to MEK or PI3K inhibition. Tumors of all three models regressed upon MEK inhibition, but showed less pronounced response to PI3K inhibition. The effect of MEK inhibition on pancreatic xenografts could be enhanced further by combined application of a PI3K inhibitor. These data provide further rationale for testing combinations of MEK and PI3K inhibitors in clinical trials comprising a patient population with pancreatic cancer harboring mutations in K-RAS.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article: Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening

    McDonald, E. Robert / Albert Lai / Alberto C. Vitari / Ali Farsidjani / Alice T. Loo / Amandine Meyer / Antoine de Weck / Audrey Kauffmann / Aurore Desplat / Avnish Kapoor / Brian Repko / Christelle Stamm / Christine Stephan / Clara Delaunay / Craig Mickanin / Daisy Flemming / David A. Ruddy / Deborah Castelletti / Dhiren Belur /
    Donald A. Dwoske / Dorothee Abramowski / Elizabeth Ackley / Elizabeth Frias / Emma Lees / Eric Billy / Fei Feng / Frances Shanahan / Francesco Hofmann / François Gauter / Frank Buxton / Frank Stegmeier / Franklin S. Chung / Giorgio G. Galli / Gregory McAllister / Gregory R. Hoffman / Hans Bitter / Iris Kao / Jan Weiler / Javad Golji / Jeffery A. Porter / Jennifer A. Johnson / JiaJia Feng / Jianjun Yu / Jilin Liu / Jing Zhang / Joel Berger / Joshua Korn / Julie L. Bernard / Justina X. Caushi / Kaitlin J. Macchi / Kalyani Gampa / Kavitha Venkatesan / Konstantinos J. Mavrakis / Kristen E. Hurov / Kristine Yu / Kristy Haas / Li Li / Malini Varadarajan / Marc Hattenberger / Marco Wallroth / Mark Stump / Marta Cortés-Cros / Mathias Jenal / Michael D. Jones / Michael R. Schlabach / Nadire Ramadan / Nicholas Keen / Odile Weber / Philippe Megel / Qiong Shen / Qiumei Liu / Ralph Tiedt / Raymond A. Pagliarini / Rebecca Billig / Richard S. Eldridge / Roger Caothien / Roland Widmer / Rosalie S. deBeaumont / Rosemary Barrett / Sandra Mollé / Saskia M. Brachmann / Serena J. Silver / Shumei Liu / Sosathya Sovath / Tami Hood / Tanja Schouwey / Tanushree Phadke / Thomas A. Perkins / Tobias Schmelzle / Typhaine Martin / Veronica Gibaja / Vic E. Myer / Volker M. Stucke / William Duong / William Forrester / William R. Sellers / Yingzi Yue / Yue Liu / Zainab Jagani / Zhenhai Gao

    Cell. 2017 July 27, v. 170

    2017  

    Abstract: Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery ...

    Abstract Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines. We describe findings of this screen, outlining the classes of cancer dependency genes and their relationships to genetic, expression, and lineage features. In addition, we describe robust gene-interaction networks recapitulating both protein complexes and functional cooperation among complexes and pathways. This dataset along with a web portal is provided to the community to assist in the discovery and translation of new therapeutic approaches for cancer.
    Keywords cell lines ; data collection ; gene deletion ; gene interaction ; humans ; Internet ; messenger RNA ; mutants ; neoplasms ; oncogenes ; RNA interference ; screening ; therapeutics ; tumor suppressor genes ; viability
    Language English
    Dates of publication 2017-0727
    Size p. 577-592.e10.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2017.07.005
    Database NAL-Catalogue (AGRICOLA)

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