ORCID Profile
0000-0002-5558-0167
Current Organisation
University College Dublin
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Publisher: Frontiers Media SA
Date: 2014
Publisher: Springer Science and Business Media LLC
Date: 10-05-2018
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-03-2023
Abstract: Gene expression noise is known to promote stochastic drug resistance through the elevated expression of in idual genes in rare cancer cells. However, we now demonstrate that chemoresistant neuroblastoma cells emerge at a much higher frequency when the influence of noise is integrated across multiple components of an apoptotic signaling network. Using a JNK activity biosensor with longitudinal high-content and in vivo intravital imaging, we identify a population of stochastic, JNK-impaired, chemoresistant cells that exist because of noise within this signaling network. Furthermore, we reveal that the memory of this initially random state is retained following chemotherapy treatment across a series of in vitro, in vivo, and patient models. Using matched PDX models established at diagnosis and relapse from in idual patients, we show that HDAC inhibitor priming cannot erase the memory of this resistant state within relapsed neuroblastomas but improves response in the first-line setting by restoring drug-induced JNK activity within the chemoresistant population of treatment-naïve tumors.
Publisher: The Company of Biologists
Date: 2016
DOI: 10.1242/JCS.179754
Abstract: Entry into mitosis is driven by the phosphorylation of thousands of substrates, under the master control of Cdk1. During entry into mitosis, Cdk1, in collaboration with MASTL kinase, represses the activity of the major mitotic protein phosphatases, PP1 and PP2A, thereby ensuring mitotic substrates remain phosphorylated. For cells to complete and exit mitosis, these phosphorylation events must be removed, and hence, phosphatase activity must be reactivated. This reactivation of phosphatase activity presumably requires the inhibition of MASTL, however, it is not currently understood how or what deactivates MASTL. In this study, we identified that PP1 is associated with and capable of partially dephosphorylating and deactivating MASTL during mitotic exit. Using mathematical modelling we were able to confirm that deactivation of MASTL is essential for mitotic exit. Furthermore, small decreases in Cdk1 activity during metaphase are sufficient to initiate the reactivation of PP1, which in turn partially deactivates MASTL to release inhibition of PP2A and hence create a feedback loop. This feedback loop drives complete deactivation of MASTL, ensuring a robust switch-like activation of phosphatase activity during mitotic exit.
Publisher: Elsevier BV
Date: 08-2020
Publisher: Wiley
Date: 19-04-2018
DOI: 10.1111/BPH.14195
Publisher: Frontiers Media SA
Date: 2012
Publisher: MDPI AG
Date: 11-05-2021
DOI: 10.3390/JPM11050395
Abstract: High-risk neuroblastoma is an aggressive childhood cancer that is characterized by high rates of chemoresistance and frequent metastatic relapse. A number of studies have characterized the genetic and epigenetic landscape of neuroblastoma, but due to a generally low mutational burden and paucity of actionable mutations, there are few options for applying a comprehensive personalized medicine approach through the use of targeted therapies. Therefore, the use of multi-agent chemotherapy remains the current standard of care for neuroblastoma, which also conceptually limits the opportunities for developing an effective and widely applicable personalized medicine approach for this disease. However, in this review we outline potential approaches for tailoring the use of chemotherapy agents to the specific molecular characteristics of in idual tumours by performing patient-specific simulations of drug-induced apoptotic signalling. By incorporating multiple layers of information about tumour-specific aberrations, including expression as well as mutation data, these models have the potential to rationalize the selection of chemotherapeutics contained within multi-agent treatment regimens and ensure the optimum response is achieved for each in idual patient.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-12-2015
DOI: 10.1126/SCISIGNAL.AAB0990
Abstract: Patient-specific modeling of a cell death–promoting pathway may lead to personalized treatment strategies.
No related grants have been discovered for Dirk Fey.