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  1. Article ; Online: Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached.

    Wilcock, Daniel J / Badrock, Andrew P / Wong, Chun W / Owen, Rhys / Guerin, Melissa / Southam, Andrew D / Johnston, Hannah / Telfer, Brian A / Fullwood, Paul / Watson, Joanne / Ferguson, Harriet / Ferguson, Jennifer / Lloyd, Gavin R / Jankevics, Andris / Dunn, Warwick B / Wellbrock, Claudia / Lorigan, Paul / Ceol, Craig / Francavilla, Chiara /
    Smith, Michael P / Hurlstone, Adam F L

    Cell reports

    2024  Volume 39, Issue 12, Page(s) 110995

    Abstract: Dysregulated cellular metabolism is a cancer hallmark for which few druggable oncoprotein targets have been identified. Increased fatty acid (FA) acquisition allows cancer cells to meet their heightened membrane biogenesis, bioenergy, and signaling needs. ...

    Abstract Dysregulated cellular metabolism is a cancer hallmark for which few druggable oncoprotein targets have been identified. Increased fatty acid (FA) acquisition allows cancer cells to meet their heightened membrane biogenesis, bioenergy, and signaling needs. Excess FAs are toxic to non-transformed cells but surprisingly not to cancer cells. Molecules underlying this cancer adaptation may provide alternative drug targets. Here, we demonstrate that diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, is frequently up-regulated in melanoma, allowing melanoma cells to tolerate excess FA. DGAT1 over-expression alone transforms p53-mutant zebrafish melanocytes and co-operates with oncogenic BRAF or NRAS for more rapid melanoma formation. Antagonism of DGAT1 induces oxidative stress in melanoma cells, which adapt by up-regulating cellular reactive oxygen species defenses. We show that inhibiting both DGAT1 and superoxide dismutase 1 profoundly suppress tumor growth through eliciting intolerable oxidative stress.
    MeSH term(s) Animals ; Diacylglycerol O-Acyltransferase/genetics ; Diacylglycerol O-Acyltransferase/metabolism ; Melanoma ; Oncogene Proteins/metabolism ; Oxidative Stress ; Reactive Oxygen Species ; Triglycerides ; Zebrafish/metabolism
    Chemical Substances Oncogene Proteins ; Reactive Oxygen Species ; Triglycerides ; Diacylglycerol O-Acyltransferase (EC 2.3.1.20)
    Language English
    Publishing date 2024-02-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2022.110995
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Osteoblasts contribute to a protective niche that supports melanoma cell proliferation and survival.

    Ferguson, Jennifer / Wilcock, Daniel J / McEntegart, Sophie / Badrock, Andrew P / Levesque, Mitch / Dummer, Reinhard / Wellbrock, Claudia / Smith, Michael P

    Pigment cell & melanoma research

    2019  Volume 33, Issue 1, Page(s) 74–85

    Abstract: Melanoma is the deadliest form of skin cancer; a primary driver of this high level of morbidity is the propensity of melanoma cells to metastasize. When malignant tumours develop distant metastatic lesions the new local tissue niche is known to impact on ...

    Abstract Melanoma is the deadliest form of skin cancer; a primary driver of this high level of morbidity is the propensity of melanoma cells to metastasize. When malignant tumours develop distant metastatic lesions the new local tissue niche is known to impact on the biology of the cancer cells. However, little is known about how different metastatic tissue sites impact on frontline targeted therapies. Intriguingly, melanoma bone lesions have significantly lower response to BRAF or MEK inhibitor therapies. Here, we have investigated how the cellular niche of the bone can support melanoma cells by stimulating growth and survival via paracrine signalling between osteoblasts and cancer cells. Melanoma cells can enhance the differentiation of osteoblasts leading to increased production of secreted ligands, including RANKL. Differentiated osteoblasts in turn can support melanoma cell proliferation and survival via the secretion of RANKL that elevates the levels of the transcription factor MITF, even in the presence of BRAF inhibitor. By blocking RANKL signalling, either via neutralizing antibodies, genetic alterations or the RANKL receptor inhibitor SPD304, the survival advantage provided by osteoblasts could be overcome.
    MeSH term(s) Cell Differentiation ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Gene Expression Regulation, Neoplastic ; Humans ; Melanoma/genetics ; Melanoma/pathology ; Microphthalmia-Associated Transcription Factor/genetics ; Microphthalmia-Associated Transcription Factor/metabolism ; Osteoblasts/pathology ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors ; Proto-Oncogene Proteins B-raf/metabolism ; RANK Ligand/metabolism ; Signal Transduction
    Chemical Substances Microphthalmia-Associated Transcription Factor ; RANK Ligand ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2019-08-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2409570-9
    ISSN 1755-148X ; 1600-0749 ; 0893-5785 ; 1755-1471
    ISSN (online) 1755-148X ; 1600-0749
    ISSN 0893-5785 ; 1755-1471
    DOI 10.1111/pcmr.12812
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2444: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models.

    Wong, Chun Wai / Evangelou, Christos / Sefton, Kieran N / Leshem, Rotem / Zhang, Wei / Gopalan, Vishaka / Chattrakarn, Sorayut / Fernandez Carro, Macarena Lucia / Uzuner, Erez / Mole, Holly / Wilcock, Daniel J / Smith, Michael P / Sergiou, Kleita / Telfer, Brian A / Isaac, Dervla T / Liu, Chang / Perl, Nicholas R / Marie, Kerrie / Lorigan, Paul /
    Williams, Kaye J / Rao, Patricia E / Nagaraju, Raghavendar T / Niepel, Mario / Hurlstone, Adam F L

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 5983

    Abstract: Resistance mechanisms to immune checkpoint blockade therapy (ICBT) limit its response duration and magnitude. Paradoxically, Interferon γ (IFNγ), a key cytokine for cellular immunity, can promote ICBT resistance. Using syngeneic mouse tumour models, we ... ...

    Abstract Resistance mechanisms to immune checkpoint blockade therapy (ICBT) limit its response duration and magnitude. Paradoxically, Interferon γ (IFNγ), a key cytokine for cellular immunity, can promote ICBT resistance. Using syngeneic mouse tumour models, we confirm that chronic IFNγ exposure confers resistance to immunotherapy targeting PD-1 (α-PD-1) in immunocompetent female mice. We observe upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in chronic IFNγ-treated cancer cell models, in patient melanoma with elevated IFNG expression, and in melanoma cell cultures from ICBT-progressing lesions characterised by elevated IFNγ signalling. Effector T cell infiltration is enhanced in tumours derived from cells pre-treated with IFNγ in immunocompetent female mice when PARP14 is pharmacologically inhibited or knocked down, while the presence of regulatory T cells is decreased, leading to restoration of α-PD-1 sensitivity. Finally, we determine that tumours which spontaneously relapse in immunocompetent female mice following α-PD-1 therapy upregulate IFNγ signalling and can also be re-sensitised upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance.
    MeSH term(s) Female ; Humans ; Animals ; Mice ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Programmed Cell Death 1 Receptor ; Interferon-gamma ; Neoplasm Recurrence, Local ; Melanoma ; Disease Models, Animal ; Poly(ADP-ribose) Polymerases
    Chemical Substances Immune Checkpoint Inhibitors ; Programmed Cell Death 1 Receptor ; Interferon-gamma (82115-62-6) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; PARP14 protein, human (EC 2.4.2.30)
    Language English
    Publishing date 2023-09-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-41737-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Cooperative behaviour and phenotype plasticity evolve during melanoma progression.

    Rowling, Emily J / Miskolczi, Zsofia / Nagaraju, Raghavendar / Wilcock, Daniel J / Wang, Ping / Telfer, Brian / Li, Yaoyong / Lasheras-Otero, Irene / Redondo-Muñoz, Marta / Sharrocks, Andrew D / Arozarena, Imanol / Wellbrock, Claudia

    Pigment cell & melanoma research

    2020  Volume 33, Issue 5, Page(s) 695–708

    Abstract: A major challenge for managing melanoma is its tumour heterogeneity based on individual co-existing melanoma cell phenotypes. These phenotypes display variable responses to standard therapies, and they drive individual steps of melanoma progression; ... ...

    Abstract A major challenge for managing melanoma is its tumour heterogeneity based on individual co-existing melanoma cell phenotypes. These phenotypes display variable responses to standard therapies, and they drive individual steps of melanoma progression; hence, understanding their behaviour is imperative. Melanoma phenotypes are defined by distinct transcriptional states, which relate to different melanocyte lineage development phases, ranging from a mesenchymal, neural crest-like to a proliferative, melanocytic phenotype. It is thought that adaptive phenotype plasticity based on transcriptional reprogramming drives melanoma progression, but at which stage individual phenotypes dominate and moreover, how they interact is poorly understood. We monitored melanocytic and mesenchymal phenotypes throughout melanoma progression and detected transcriptional reprogramming at different stages, with a gain in mesenchymal traits in circulating melanoma cells (CTCs) and proliferative features in metastatic tumours. Intriguingly, we found that distinct phenotype populations interact in a cooperative manner, which generates tumours of greater "fitness," supports CTCs and expands organotropic cues in metastases. Fibronectin, expressed in mesenchymal cells, acts as key player in cooperativity and promotes survival of melanocytic cells. Our data reveal an important role for inter-phenotype communications at various stages of disease progression, suggesting these communications could act as therapeutic target.
    MeSH term(s) Adaptation, Physiological ; Animals ; Cell Communication ; Cell Line, Tumor ; Cell Proliferation ; Disease Progression ; Fibronectins/metabolism ; Humans ; Melanocytes/pathology ; Melanoma/pathology ; Mesoderm/pathology ; Mice ; Neoplasm Metastasis ; Neoplastic Cells, Circulating/pathology ; Phenotype
    Chemical Substances Fibronectins
    Language English
    Publishing date 2020-03-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2409570-9
    ISSN 1755-148X ; 1600-0749 ; 0893-5785 ; 1755-1471
    ISSN (online) 1755-148X ; 1600-0749
    ISSN 0893-5785 ; 1755-1471
    DOI 10.1111/pcmr.12873
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2444: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  5. Article ; Online: The putative tumour suppressor protein Latexin is secreted by prostate luminal cells and is downregulated in malignancy.

    Seed, Robert I / Taurozzi, Alberto J / Wilcock, Daniel J / Nappo, Giovanna / Erb, Holger H H / Read, Martin L / Gurney, Mark / Archer, Leanne K / Ito, Saburo / Rumsby, Martin G / Petrie, John L / Clayton, Aled / Maitland, Norman J / Collins, Anne T

    Scientific reports

    2019  Volume 9, Issue 1, Page(s) 5120

    Abstract: Loss of latexin (LXN) expression negatively correlates with the prognosis of several human cancers. Despite association with numerous processes including haematopoietic stem cell (HSC) fate, inflammation and tumour suppression, a clearly defined ... ...

    Abstract Loss of latexin (LXN) expression negatively correlates with the prognosis of several human cancers. Despite association with numerous processes including haematopoietic stem cell (HSC) fate, inflammation and tumour suppression, a clearly defined biological role for LXN is still lacking. Therefore, we sought to understand LXN expression and function in the normal and malignant prostate to assess its potential as a therapeutic target. Our data demonstrate that LXN is highly expressed in normal prostate luminal cells but downregulated in high Gleason grade cancers. LXN protein is both cytosolic and secreted by prostate cells and expression is directly and potently upregulated by all-trans retinoic acid (atRA). Whilst overexpression of LXN in prostate epithelial basal cells did not affect cell fate, LXN overexpression in the luminal cancer line LNCaP reduced plating efficiency. Transcriptome analysis revealed that LXN overexpression had no direct effects on gene expression but had significant indirect effects on important genes involved in both retinoid metabolism and IFN-associated inflammatory responses. These data highlight a potential role for LXN in retinoid signaling and inflammatory pathways. Investigating the effects of LXN on immune cell function in the tumour microenvironment (TME) may reveal how observed intratumoural loss of LXN affects the prognosis of many adenocarcinomas.
    MeSH term(s) Down-Regulation ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Nerve Tissue Proteins/biosynthesis ; Nerve Tissue Proteins/genetics ; PC-3 Cells ; Prostate/metabolism ; Prostate/pathology ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Tumor Suppressor Proteins/biosynthesis ; Tumor Suppressor Proteins/genetics
    Chemical Substances Lxn protein, human ; Nerve Tissue Proteins ; Tumor Suppressor Proteins
    Language English
    Publishing date 2019-03-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-019-41379-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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