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  1. Article ; Online: Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies

    Sophia A Wild / Ian G Cannell / Ashley Nicholls / Katarzyna Kania / Dario Bressan / CRUK IMAXT Grand Challenge Team / Gregory J Hannon / Kirsty Sawicka

    eLife, Vol

    2022  Volume 11

    Abstract: Tumour heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained ... ...

    Abstract Tumour heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained challenging. Here, we utilise clonal transcriptomics with WILD-seq; Wholistic Interrogation of Lineage Dynamics by sequencing, in mouse models of triple-negative breast cancer (TNBC) to understand response and resistance to therapy, including BET bromodomain inhibition and taxane-based chemotherapy. These analyses revealed oxidative stress protection by NRF2 as a major mechanism of taxane resistance and led to the discovery that our tumour models are collaterally sensitive to asparagine deprivation therapy using the clinical stage drug L-asparaginase after frontline treatment with docetaxel. In summary, clonal transcriptomics with WILD-seq identifies mechanisms of resistance to chemotherapy that are also operative in patients and pin points asparagine bioavailability as a druggable vulnerability of taxane-resistant lineages.
    Keywords tumor heterogeneity ; cancer therapy ; lineage tracing ; single cell genomics ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2022-12-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Transite

    Konstantin Krismer / Molly A. Bird / Shohreh Varmeh / Erika D. Handly / Anna Gattinger / Thomas Bernwinkler / Daniel A. Anderson / Andreas Heinzel / Brian A. Joughin / Yi Wen Kong / Ian G. Cannell / Michael B. Yaffe

    Cell Reports, Vol 32, Iss 8, Pp 108064- (2020)

    A Computational Motif-Based Analysis Platform That Identifies RNA-Binding Proteins Modulating Changes in Gene Expression

    2020  

    Abstract: Summary: RNA-binding proteins (RBPs) play critical roles in regulating gene expression by modulating splicing, RNA stability, and protein translation. Stimulus-induced alterations in RBP function contribute to global changes in gene expression, but ... ...

    Abstract Summary: RNA-binding proteins (RBPs) play critical roles in regulating gene expression by modulating splicing, RNA stability, and protein translation. Stimulus-induced alterations in RBP function contribute to global changes in gene expression, but identifying which RBPs are responsible for the observed changes remains an unmet need. Here, we present Transite, a computational approach that systematically infers RBPs influencing gene expression through changes in RNA stability and degradation. As a proof of principle, we apply Transite to RNA expression data from human patients with non-small-cell lung cancer whose tumors were sampled at diagnosis or after recurrence following treatment with platinum-based chemotherapy. Transite implicates known RBP regulators of the DNA damage response and identifies hnRNPC as a new modulator of chemotherapeutic resistance, which we subsequently validated experimentally. Transite serves as a framework for the identification of RBPs that drive cell-state transitions and adds additional value to the vast collection of publicly available gene expression datasets.
    Keywords RNA-binding proteins ; post-transcriptional regulation ; sequence motifs ; chemotherapy ; DNA damage response ; Biology (General) ; QH301-705.5
    Subject code 612 ; 570
    Language English
    Publishing date 2020-08-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and p53 in the DNA Damage Response In Vivo

    Sandra Morandell / H. Christian Reinhardt / Ian G. Cannell / Jacob S. Kim / Daniela M. Ruf / Tanya Mitra / Anthony D. Couvillon / Tyler Jacks / Michael B. Yaffe

    Cell Reports, Vol 5, Iss 4, Pp 868-

    2013  Volume 877

    Abstract: A fundamental limitation in devising new therapeutic strategies for killing cancer cells with DNA damaging agents is the need to identify synthetic lethal interactions between tumor-specific mutations and components of the DNA damage response (DDR) in ... ...

    Abstract A fundamental limitation in devising new therapeutic strategies for killing cancer cells with DNA damaging agents is the need to identify synthetic lethal interactions between tumor-specific mutations and components of the DNA damage response (DDR) in vivo. The stress-activated p38 mitogen-activated protein kinase (MAPK)/MAPKAP kinase-2 (MK2) pathway is a critical component of the DDR network in p53-deficient tumor cells in vitro. To explore the relevance of this pathway for cancer therapy in vivo, we developed a specific gene targeting strategy in which Cre-mediated recombination simultaneously creates isogenic MK2-proficient and MK2-deficient tumors within a single animal. This allows direct identification of MK2 synthetic lethality with mutations that promote tumor development or control response to genotoxic treatment. In an autochthonous model of non-small-cell lung cancer (NSCLC), we demonstrate that MK2 is responsible for resistance of p53-deficient tumors to cisplatin, indicating synthetic lethality between p53 and MK2 can successfully be exploited for enhanced sensitization of tumors to DNA-damaging chemotherapeutics in vivo.
    Keywords Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2013-11-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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