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  1. Article: Functional Characterisation of the ATOH1 Molecular Subtype Indicates a Pro-Metastatic Role in Small Cell Lung Cancer.

    Catozzi, Alessia / Peiris-Pagès, Maria / Humphrey, Sam / Revill, Mitchell / Morgan, Derrick / Roebuck, Jordan / Chen, Yitao / Davies-Williams, Bethan / Lallo, Alice / Galvin, Melanie / Pearce, Simon P / Kerr, Alastair / Priest, Lynsey / Foy, Victoria / Carter, Mathew / Caeser, Rebecca / Chan, Joseph / Rudin, Charles M / Blackhall, Fiona /
    Frese, Kristopher K / Dive, Caroline / Simpson, Kathryn L

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Molecular subtypes of Small Cell Lung Cancer (SCLC) have been described based on differential expression of transcription factors (TFs) ...

    Abstract Molecular subtypes of Small Cell Lung Cancer (SCLC) have been described based on differential expression of transcription factors (TFs)
    Language English
    Publishing date 2024-02-17
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.16.580247
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The Rare YAP1 Subtype of SCLC Revisited in a Biobank of 39 Circulating Tumor Cell Patient Derived Explant Models: A Brief Report.

    Pearsall, Sarah M / Humphrey, Sam / Revill, Mitchell / Morgan, Derrick / Frese, Kristopher K / Galvin, Melanie / Kerr, Alastair / Carter, Mathew / Priest, Lynsey / Blackhall, Fiona / Simpson, Kathryn L / Dive, Caroline

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

    2020  Volume 15, Issue 12, Page(s) 1836–1843

    Abstract: Introduction: Recent consensus defines four SCLC subtypes on the basis of transcription factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is associated with "neuroendocrine (NE)-low" cells among SCLC cell lines and patient ... ...

    Abstract Introduction: Recent consensus defines four SCLC subtypes on the basis of transcription factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is associated with "neuroendocrine (NE)-low" cells among SCLC cell lines and patient samples. We evaluated YAP1 in 39 patients with phenotypically diverse circulating tumor cell-derived explant (CDX) models and revisited YAP1 in terms of prevalence, cell phenotype, and intertumor and intratumor heterogeneity.
    Methods: YAP1 transcript and protein expression were assessed by RNA sequencing and immunohistochemistry or multiplexed immunofluorescence of NE and non-NE CDX subpopulations. Physically separated NE and non-NE CDX ex vivo culture lysates were Western blotted for YAP1, NE marker SYP, and AXL.
    Results: RNA sequencing normalized for the four subtype transcription factors identified YAP1 expression in 14 of 39 CDX. A total of 10 CDX expressed YAP1 protein, and eight had strong YAP1 expression confined to rare non-NE cell clusters. This was confirmed in ex vivo CDX cultures in which adherent non-NE cells lacking SYP expression expressed YAP1. However, in two CDX, weaker cellular YAP1 expression was observed, widely dispersed in SYP-positive NE cells.
    Conclusions: YAP1 was predominantly expressed in non-NE cell clusters in SCLC CDX, but two of 39 CDX expressed YAP1 in NE cells. CDX22P, with relatively high YAP1 expression, is an ASCL1 NE subtype with a low NE score and an outlier within this subtype in our CDX biobank. These descriptive data reveal subtly different YAP1 expression profiles, paving the way for functional studies to compare YAP1 signaling in non-NE and low NE cell contexts for potentially personalized therapeutic approaches.
    MeSH term(s) Adaptor Proteins, Signal Transducing/genetics ; Biological Specimen Banks ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/genetics ; Neoplastic Cells, Circulating ; Transcription Factors/genetics ; YAP-Signaling Proteins
    Chemical Substances Adaptor Proteins, Signal Transducing ; Transcription Factors ; YAP-Signaling Proteins ; YAP1 protein, human
    Language English
    Publishing date 2020-07-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2432037-7
    ISSN 1556-1380 ; 1556-0864
    ISSN (online) 1556-1380
    ISSN 1556-0864
    DOI 10.1016/j.jtho.2020.07.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 652: Show issues

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  3. Article ; Online: Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer.

    Schenk, Maximilian W / Humphrey, Sam / Hossain, A S Md Mukarram / Revill, Mitchell / Pearsall, Sarah / Lallo, Alice / Brown, Stewart / Bratt, Samuel / Galvin, Melanie / Descamps, Tine / Zhou, Cong / Pearce, Simon P / Priest, Lynsey / Greenhalgh, Michelle / Chaturvedi, Anshuman / Kerr, Alastair / Blackhall, Fiona / Dive, Caroline / Frese, Kristopher K

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 6652

    Abstract: Small cell lung cancer (SCLC) has a 5-year survival rate of <7%. Rapid emergence of acquired resistance to standard platinum-etoposide chemotherapy is common and improved therapies are required for this recalcitrant tumour. We exploit six paired pre- ... ...

    Abstract Small cell lung cancer (SCLC) has a 5-year survival rate of <7%. Rapid emergence of acquired resistance to standard platinum-etoposide chemotherapy is common and improved therapies are required for this recalcitrant tumour. We exploit six paired pre-treatment and post-chemotherapy circulating tumour cell patient-derived explant (CDX) models from donors with extensive stage SCLC to investigate changes at disease progression after chemotherapy. Soluble guanylate cyclase (sGC) is recurrently upregulated in post-chemotherapy progression CDX models, which correlates with acquired chemoresistance. Expression and activation of sGC is regulated by Notch and nitric oxide (NO) signalling with downstream activation of protein kinase G. Genetic targeting of sGC or pharmacological inhibition of NO synthase re-sensitizes a chemoresistant CDX progression model in vivo, revealing this pathway as a mediator of chemoresistance and potential vulnerability of relapsed SCLC.
    MeSH term(s) Animals ; Cyclic GMP-Dependent Protein Kinases/metabolism ; Disease Models, Animal ; Disease Progression ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Enzyme Inhibitors/therapeutic use ; Etoposide/therapeutic use ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mice ; Neoplastic Cells, Circulating/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/antagonists & inhibitors ; Receptors, Notch/metabolism ; Signal Transduction/genetics ; Small Cell Lung Carcinoma/drug therapy ; Small Cell Lung Carcinoma/metabolism ; Small Cell Lung Carcinoma/pathology ; Soluble Guanylyl Cyclase/genetics ; Soluble Guanylyl Cyclase/metabolism
    Chemical Substances Enzyme Inhibitors ; Receptors, Notch ; Nitric Oxide (31C4KY9ESH) ; Etoposide (6PLQ3CP4P3) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Cyclic GMP-Dependent Protein Kinases (EC 2.7.11.12) ; Soluble Guanylyl Cyclase (EC 4.6.1.2)
    Language English
    Publishing date 2021-11-17
    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/s41467-021-26823-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity.

    Simpson, Kathryn L / Stoney, Ruth / Frese, Kristopher K / Simms, Nicole / Rowe, William / Pearce, Simon P / Humphrey, Sam / Booth, Laura / Morgan, Derrick / Dynowski, Marek / Trapani, Francesca / Catozzi, Alessia / Revill, Mitchell / Helps, Thomas / Galvin, Melanie / Girard, Luc / Nonaka, Daisuke / Carter, Louise / Krebs, Matthew G /
    Cook, Natalie / Carter, Mathew / Priest, Lynsey / Kerr, Alastair / Gazdar, Adi F / Blackhall, Fiona / Dive, Caroline

    Nature cancer

    2020  Volume 1, Issue 4, Page(s) 437–451

    Abstract: Although small cell lung cancer (SCLC) is treated as a homogeneous disease, biopsies and preclinical models reveal heterogeneity in transcriptomes and morphology. SCLC subtypes were recently defined by neuroendocrine transcription factor (NETF) ... ...

    Abstract Although small cell lung cancer (SCLC) is treated as a homogeneous disease, biopsies and preclinical models reveal heterogeneity in transcriptomes and morphology. SCLC subtypes were recently defined by neuroendocrine transcription factor (NETF) expression. Circulating-tumor-cell-derived explant models (CDX) recapitulate donor patients' tumor morphology, diagnostic NE marker expression and chemotherapy responses. We describe a biobank of 38 CDX models, including six CDX pairs generated pretreatment and at disease progression revealing complex intra- and intertumoral heterogeneity. Transcriptomic analysis confirmed three of four previously described subtypes based on ASCL1, NEUROD1 and POU2F3 expression and identified a previously unreported subtype based on another NETF, ATOH1. We document evolution during disease progression exemplified by altered MYC and NOTCH gene expression, increased 'variant' cell morphology, and metastasis without strong evidence of epithelial to mesenchymal transition. This CDX biobank provides a research resource to facilitate SCLC personalized medicine.
    MeSH term(s) Biological Specimen Banks ; Disease Progression ; Epithelial-Mesenchymal Transition ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/genetics ; Small Cell Lung Carcinoma/genetics
    Language English
    Publishing date 2020-04-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2662-1347
    ISSN (online) 2662-1347
    DOI 10.1038/s43018-020-0046-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt's lymphoma anti-tumor activity.

    Curtis, Nicola J / Mooney, Lorraine / Hopcroft, Lorna / Michopoulos, Filippos / Whalley, Nichola / Zhong, Haihong / Murray, Clare / Logie, Armelle / Revill, Mitchell / Byth, Kate F / Benjamin, Amanda D / Firth, Mike A / Green, Stephen / Smith, Paul D / Critchlow, Susan E

    Oncotarget

    2017  Volume 8, Issue 41, Page(s) 69219–69236

    Abstract: Tumors frequently display a glycolytic phenotype with increased flux through glycolysis and concomitant synthesis of lactate. To maintain glycolytic flux and prevent intracellular acidification, tumors efflux lactate via lactate transporters (MCT1-4). ... ...

    Abstract Tumors frequently display a glycolytic phenotype with increased flux through glycolysis and concomitant synthesis of lactate. To maintain glycolytic flux and prevent intracellular acidification, tumors efflux lactate via lactate transporters (MCT1-4). Inhibitors of lactate transport have the potential to inhibit glycolysis and tumor growth. We developed a small molecule inhibitor of MCT1 (AZD3965) and assessed its activity across a panel of cell lines. We explored its antitumor activity as monotherapy and in combination with doxorubicin or rituximab. AZD3965 is a potent inhibitor of MCT1 with activity against MCT2 but selectivity over MCT3 and MCT4.
    Language English
    Publishing date 2017-09-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.18215
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS.

    Ross, Sarah J / Revenko, Alexey S / Hanson, Lyndsey L / Ellston, Rebecca / Staniszewska, Anna / Whalley, Nicky / Pandey, Sanjay K / Revill, Mitchell / Rooney, Claire / Buckett, Linda K / Klein, Stephanie K / Hudson, Kevin / Monia, Brett P / Zinda, Michael / Blakey, David C / Lyne, Paul D / Macleod, A Robert

    Science translational medicine

    2017  Volume 9, Issue 394

    Abstract: Activating mutations ... ...

    Abstract Activating mutations in
    Language English
    Publishing date 2017-06-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.aal5253
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6941: Show issues Location:
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