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  1. Article ; Online: PyMT-Maclow

    Robin M H Rumney / Seth B Coffelt / Terence A Neale / Sandeep Dhayade / Gillian M Tozer / Gaynor Miller

    PLoS ONE, Vol 12, Iss 12, p e

    A novel, inducible, murine model for determining the role of CD68 positive cells in breast tumor development.

    2017  Volume 0188591

    Abstract: CD68+ tumor-associated macrophages (TAMs) are pro-tumorigenic, pro-angiogenic and are associated with decreased survival rates in patients with cancer, including breast cancer. Non-specific models of macrophage ablation reduce the number of TAMs and ... ...

    Abstract CD68+ tumor-associated macrophages (TAMs) are pro-tumorigenic, pro-angiogenic and are associated with decreased survival rates in patients with cancer, including breast cancer. Non-specific models of macrophage ablation reduce the number of TAMs and limit the development of mammary tumors. However, the lack of specificity and side effects associated with these models compromise their reliability. We hypothesized that specific and controlled macrophage depletion would provide precise data on the effects of reducing TAM numbers on tumor development. In this study, the MacLow mouse model of doxycycline-inducible and selective CD68+ macrophage depletion was crossed with the murine mammary tumor virus (MMTV)-Polyoma virus middle T antigen (PyMT) mouse model of spontaneous ductal breast adenocarcinoma to generate the PyMT-MacLow line. In doxycycline-treated PyMT-MacLow mice, macrophage numbers were decreased in areas surrounding tumors by 43%. Reducing the number of macrophages by this level delayed tumor progression, generated less proliferative tumors, decreased the vascularization of carcinomas and down-regulated the expression of many pro-angiogenic genes. These results demonstrate that depleting CD68+ macrophages in an inducible and selective manner delays the development of mammary tumors and that the PyMT-MacLow model is a useful and unique tool for studying the role of TAMs in breast cancer.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2017-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: A Unique Panel of Patient-Derived Cutaneous Squamous Cell Carcinoma Cell Lines Provides a Preclinical Pathway for Therapeutic Testing

    Sakinah Hassan / Karin J. Purdie / Jun Wang / Catherine A. Harwood / Charlotte M. Proby / Celine Pourreyron / Nikol Mladkova / Ai Nagano / Sandeep Dhayade / Dimitris Athineos / Matthew Caley / Viviana Mannella / Karen Blyth / Gareth J. Inman / Irene M. Leigh

    International Journal of Molecular Sciences, Vol 20, Iss 14, p

    2019  Volume 3428

    Abstract: Background: Cutaneous squamous cell carcinoma (cSCC) incidence continues to rise with increasing morbidity and mortality, with limited treatment options for advanced disease. Future improvements in targeted therapy will rely on advances in genomic/ ... ...

    Abstract Background: Cutaneous squamous cell carcinoma (cSCC) incidence continues to rise with increasing morbidity and mortality, with limited treatment options for advanced disease. Future improvements in targeted therapy will rely on advances in genomic/transcriptomic understanding and the use of model systems for basic research. We describe here the panel of 16 primary and metastatic cSCC cell lines developed and characterised over the past three decades in our laboratory in order to provide such a resource for future preclinical research and drug screening. Methods: Primary keratinocytes were isolated from cSCC tumours and metastases, and cell lines were established. These were characterised using short tandem repeat (STR) profiling and genotyped by whole exome sequencing. Multiple in vitro assays were performed to document their morphology, growth characteristics, migration and invasion characteristics, and in vivo xenograft growth. Results: STR profiles of the cSCC lines allow the confirmation of their unique identity. Phylogenetic trees derived from exome sequence analysis of the matched primary and metastatic lines provide insight into the genetic basis of disease progression. The results of in vivo and in vitro analyses allow researchers to select suitable cell lines for specific experimentation. Conclusions: There are few well-characterised cSCC lines available for widespread preclinical experimentation and drug screening. The described cSCC cell line panel provides a critical tool for in vitro and in vivo experimentation.
    Keywords squamous cell carcinoma ; cutaneous ; in vitro ; keratinocytes ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 571
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells

    Emmanuel Dornier / Nicolas Rabas / Louise Mitchell / David Novo / Sandeep Dhayade / Sergi Marco / Gillian Mackay / David Sumpton / Maria Pallares / Colin Nixon / Karen Blyth / Iain R. Macpherson / Elena Rainero / Jim C. Norman

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 14

    Abstract: Glutamine metabolism is well known to support tumour growth. Here the authors show that cancer cells also utilize glutamine to promote invasiveness by converting it to glutamate, which upon secretion activates metabotropic glutamate receptors to ... ...

    Abstract Glutamine metabolism is well known to support tumour growth. Here the authors show that cancer cells also utilize glutamine to promote invasiveness by converting it to glutamate, which upon secretion activates metabotropic glutamate receptors to stimulate matrix metalloproteases recycling to the cell surface.
    Keywords Science ; Q
    Language English
    Publishing date 2017-12-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells

    Emmanuel Dornier / Nicolas Rabas / Louise Mitchell / David Novo / Sandeep Dhayade / Sergi Marco / Gillian Mackay / David Sumpton / Maria Pallares / Colin Nixon / Karen Blyth / Iain R. Macpherson / Elena Rainero / Jim C. Norman

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 14

    Abstract: Glutamine metabolism is well known to support tumour growth. Here the authors show that cancer cells also utilize glutamine to promote invasiveness by converting it to glutamate, which upon secretion activates metabotropic glutamate receptors to ... ...

    Abstract Glutamine metabolism is well known to support tumour growth. Here the authors show that cancer cells also utilize glutamine to promote invasiveness by converting it to glutamate, which upon secretion activates metabotropic glutamate receptors to stimulate matrix metalloproteases recycling to the cell surface.
    Keywords Science ; Q
    Language English
    Publishing date 2017-12-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Increased formate overflow is a hallmark of oxidative cancer

    Johannes Meiser / Anne Schuster / Matthias Pietzke / Johan Vande Voorde / Dimitris Athineos / Kristell Oizel / Guillermo Burgos-Barragan / Niek Wit / Sandeep Dhayade / Jennifer P. Morton / Emmanuel Dornier / David Sumpton / Gillian M. Mackay / Karen Blyth / Ketan J. Patel / Simone P. Niclou / Alexei Vazquez

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 12

    Abstract: Serine catabolism to formate supplies one-carbon units for biosynthesis. Here the authors show that formate production in murine cancers with high oxidative metabolism exceeds the biosynthetic demand and that high formate levels promotes invasion of ... ...

    Abstract Serine catabolism to formate supplies one-carbon units for biosynthesis. Here the authors show that formate production in murine cancers with high oxidative metabolism exceeds the biosynthetic demand and that high formate levels promotes invasion of cancer cells.
    Keywords Science ; Q
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Increased formate overflow is a hallmark of oxidative cancer

    Johannes Meiser / Anne Schuster / Matthias Pietzke / Johan Vande Voorde / Dimitris Athineos / Kristell Oizel / Guillermo Burgos-Barragan / Niek Wit / Sandeep Dhayade / Jennifer P. Morton / Emmanuel Dornier / David Sumpton / Gillian M. Mackay / Karen Blyth / Ketan J. Patel / Simone P. Niclou / Alexei Vazquez

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 12

    Abstract: Serine catabolism to formate supplies one-carbon units for biosynthesis. Here the authors show that formate production in murine cancers with high oxidative metabolism exceeds the biosynthetic demand and that high formate levels promotes invasion of ... ...

    Abstract Serine catabolism to formate supplies one-carbon units for biosynthesis. Here the authors show that formate production in murine cancers with high oxidative metabolism exceeds the biosynthetic demand and that high formate levels promotes invasion of cancer cells.
    Keywords Science ; Q
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth

    Sandeep Dhayade / Susanne Kaesler / Tobias Sinnberg / Hyazinth Dobrowinski / Stefanie Peters / Ulrike Naumann / He Liu / Robert E. Hunger / Martin Thunemann / Tilo Biedermann / Birgit Schittek / Hans-Uwe Simon / Susanne Feil / Robert Feil

    Cell Reports, Vol 14, Iss 11, Pp 2599-

    2016  Volume 2610

    Abstract: Sildenafil, an inhibitor of the cGMP-degrading phosphodiesterase 5 that is used to treat erectile dysfunction, has been linked to an increased risk of melanoma. Here, we have examined the potential connection between cGMP-dependent signaling cascades and ...

    Abstract Sildenafil, an inhibitor of the cGMP-degrading phosphodiesterase 5 that is used to treat erectile dysfunction, has been linked to an increased risk of melanoma. Here, we have examined the potential connection between cGMP-dependent signaling cascades and melanoma growth. Using a combination of biochemical assays and real-time monitoring of melanoma cells, we report a cGMP-dependent growth-promoting pathway in murine and human melanoma cells. We document that C-type natriuretic peptide (CNP), a ligand of the membrane-bound guanylate cyclase B, enhances the activity of cGMP-dependent protein kinase I (cGKI) in melanoma cells by increasing the intracellular levels of cGMP. Activation of this cGMP pathway promotes melanoma cell growth and migration in a p44/42 MAPK-dependent manner. Sildenafil treatment further increases intracellular cGMP concentrations, potentiating activation of this pathway. Collectively, our data identify this cGMP-cGKI pathway as the link between sildenafil usage and increased melanoma risk.
    Keywords Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2016-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation

    Vinay Bulusu / Sergey Tumanov / Evdokia Michalopoulou / Niels J. van den Broek / Gillian MacKay / Colin Nixon / Sandeep Dhayade / Zachary T. Schug / Johan Vande Voorde / Karen Blyth / Eyal Gottlieb / Alexei Vazquez / Jurre J. Kamphorst

    Cell Reports, Vol 18, Iss 3, Pp 647-

    2017  Volume 658

    Abstract: Acetyl-CoA is a key metabolic intermediate with an important role in transcriptional regulation. The nuclear-cytosolic acetyl-CoA synthetase 2 (ACSS2) was found to sustain the growth of hypoxic tumor cells. It generates acetyl-CoA from acetate, but ... ...

    Abstract Acetyl-CoA is a key metabolic intermediate with an important role in transcriptional regulation. The nuclear-cytosolic acetyl-CoA synthetase 2 (ACSS2) was found to sustain the growth of hypoxic tumor cells. It generates acetyl-CoA from acetate, but exactly which pathways it supports is not fully understood. Here, quantitative analysis of acetate metabolism reveals that ACSS2 fulfills distinct functions depending on its cellular location. Exogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and ACSS2 supports lipogenesis. The mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to only sparingly contribute to histone acetylation. Surprisingly, oxygen and serum limitation increase nuclear localization of ACSS2. We find that nuclear ACSS2 recaptures acetate released from histone deacetylation for recycling by histone acetyltransferases. Our work provides evidence for limited equilibration between nuclear and cytosolic acetyl-CoA and demonstrates that ACSS2 retains acetate to maintain histone acetylation.
    Keywords acetate ; acetyl-CoA synthetase 2 ; cancer metabolism ; enzyme localization ; histone acetylation ; histone deacetylation ; hypoxia ; lipogenesis ; metabolite compartmentalization ; stable isotope tracing ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2017-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: cGMP-dependent protein kinase contributes to hydrogen sulfide-stimulated vasorelaxation.

    Mariarosaria Bucci / Andreas Papapetropoulos / Valentina Vellecco / Zongmin Zhou / Altaany Zaid / Panagiotis Giannogonas / Anna Cantalupo / Sandeep Dhayade / Katia P Karalis / Rui Wang / Robert Feil / Giuseppe Cirino

    PLoS ONE, Vol 7, Iss 12, p e

    2012  Volume 53319

    Abstract: A growing body of evidence suggests that hydrogen sulfide (H₂S) is a signaling molecule in mammalian cells. In the cardiovascular system, H₂S enhances vasodilation and angiogenesis. H₂S-induced vasodilation is hypothesized to occur through ATP-sensitive ... ...

    Abstract A growing body of evidence suggests that hydrogen sulfide (H₂S) is a signaling molecule in mammalian cells. In the cardiovascular system, H₂S enhances vasodilation and angiogenesis. H₂S-induced vasodilation is hypothesized to occur through ATP-sensitive potassium channels (K(ATP)); however, we recently demonstrated that it also increases cGMP levels in tissues. Herein, we studied the involvement of cGMP-dependent protein kinase-I in H₂S-induced vasorelaxation. The effect of H₂S on vessel tone was studied in phenylephrine-contracted aortic rings with or without endothelium. cGMP levels were determined in cultured cells or isolated vessel by enzyme immunoassay. Pretreatment of aortic rings with sildenafil attenuated NaHS-induced relaxation, confirming previous findings that H₂S is a phosphodiesterase inhibitor. In addition, vascular tissue levels of cGMP in cystathionine gamma lyase knockouts were lower than those in wild-type control mice. Treatment of aortic rings with NaHS, a fast releasing H₂S donor, enhanced phosphorylation of vasodilator-stimulated phosphoprotein in a time-dependent manner, suggesting that cGMP-dependent protein kinase (PKG) is activated after exposure to H₂S. Incubation of aortic rings with a PKG-I inhibitor (DT-2) attenuated NaHS-stimulated relaxation. Interestingly, vasodilatory responses to a slowly releasing H₂S donor (GYY 4137) were unaffected by DT-2, suggesting that this donor dilates mouse aorta through PKG-independent pathways. Dilatory responses to NaHS and L-cysteine (a substrate for H₂S production) were reduced in vessels of PKG-I knockout mice (PKG-I⁻/⁻). Moreover, glibenclamide inhibited NaHS-induced vasorelaxation in vessels from wild-type animals, but not PKG-I⁻/⁻, suggesting that there is a cross-talk between K(ATP) and PKG. Our results confirm the role of cGMP in the vascular responses to NaHS and demonstrate that genetic deletion of PKG-I attenuates NaHS and L-cysteine-stimulated vasodilation.
    Keywords Medicine ; R ; Science ; Q
    Subject code 571
    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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  10. Article ; Online: Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity

    Juan R. Hernandez-Fernaud / Elena Ruengeler / Andrea Casazza / Lisa J. Neilson / Ellie Pulleine / Alice Santi / Shehab Ismail / Sergio Lilla / Sandeep Dhayade / Iain R. MacPherson / Iain McNeish / Darren Ennis / Hala Ali / Fernanda G. Kugeratski / Heba Al Khamici / Maartje van den Biggelaar / Peter V.E. van den Berghe / Catherine Cloix / Laura McDonald /
    David Millan / Aoisha Hoyle / Anna Kuchnio / Peter Carmeliet / Stella M. Valenzuela / Karen Blyth / Huabing Yin / Massimiliano Mazzone / Jim C. Norman / Sara Zanivan

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 17

    Abstract: The secretome from cancer and stromal cells contributes to the creation of a microenvironment, which in turn contributes to invasion and angiogenesis. Here, the authors compare the secretomes of immortalized normal fibroblasts and cancer-derived ... ...

    Abstract The secretome from cancer and stromal cells contributes to the creation of a microenvironment, which in turn contributes to invasion and angiogenesis. Here, the authors compare the secretomes of immortalized normal fibroblasts and cancer-derived fibroblast and identify CLIC3 as a driver of cancer progression.
    Keywords Science ; Q
    Language English
    Publishing date 2017-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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