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203 results on '"Muir, Morwenna"'

3. MYC sensitises cells to apoptosis by driving energetic demand

Author

Edwards-Hicks, Joy, Su, Huizhong, Mangolini, Maurizio, Yoneten, Kubra K., Wills, Jimi, Rodriguez-Blanco, Giovanny, Young, Christine, Cho, Kevin, Barker, Heather, Muir, Morwenna, Guerrieri, Ania Naila, Li, Xue-Feng, White, Rachel, Manasterski, Piotr, Mandrou, Elena, Wills, Karen, Chen, Jingyu, Abraham, Emily, Sateri, Kianoosh, Qian, Bin-Zhi, Bankhead, Peter, Arends, Mark, Gammoh, Noor, von Kriegsheim, Alex, Patti, Gary J., Sims, Andrew H., Acosta, Juan Carlos, Brunton, Valerie, Kranc, Kamil R., Christophorou, Maria, Pearce, Erika L., Ringshausen, Ingo, and Finch, Andrew J.

Published
2022
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7. A novel ILK/STAT3 pathway controls plasticity in a neural stem cell model of glioblastoma.

Author

Loftus, Alexander E.P., primary, Romano, Marianna S., additional, Nguyen Phuong, Anh, additional, Muir, Morwenna T., additional, Dawson, John C., additional, Avalle, Lidia, additional, Douglas, Adam T., additional, Mort, Richard L., additional, Byron, Adam, additional, Carragher, Neil O., additional, Pollard, Steven M., additional, Brunton, Valerie G., additional, and Frame, Margaret C., additional

Published
2023
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8. CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions

Author

Zimmermann, Michal, Murina, Olga, Reijns, Martin A. M., Agathanggelou, Angelo, Challis, Rachel, Tarnauskaite, Zygimante, and Muir, Morwenna

Subjects
DNA polymerases -- Physiological aspects, CRISPR-Cas systems -- Usage, Ribonucleotides -- Physiological aspects -- Genetic aspects, Ribonuclease, Cancer treatment, Prostate cancer, DNA replication, Leukemia, Cancer, Antineoplastic agents, Genomics, Biotechnology, Ionizing radiation, DNA, Genes, Monosaccharides, Cancer metastasis, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The observation that BRCA1- and BRCA2-deficient cells are sensitive to inhibitors of poly(ADP-ribose) polymerase (PARP) has spurred the development of cancer therapies that use these inhibitors to target deficiencies in homologous recombination.sup.1. The cytotoxicity of PARP inhibitors depends on PARP trapping, the formation of non-covalent protein-DNA adducts composed of inhibited PARP1 bound to DNA lesions of unclear origins.sup.1-4. To address the nature of such lesions and the cellular consequences of PARP trapping, we undertook three CRISPR (clustered regularly interspersed palindromic repeats) screens to identify genes and pathways that mediate cellular resistance to olaparib, a clinically approved PARP inhibitor.sup.1. Here we present a high-confidence set of 73 genes, which when mutated cause increased sensitivity to PARP inhibitors. In addition to an expected enrichment for genes related to homologous recombination, we discovered that mutations in all three genes encoding ribonuclease H2 sensitized cells to PARP inhibition. We establish that the underlying cause of the PARP-inhibitor hypersensitivity of cells deficient in ribonuclease H2 is impaired ribonucleotide excision repair.sup.5. Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by topoisomerase 1, resulting in PARP-trapping lesions that impede DNA replication and endanger genome integrity. We conclude that genomic ribonucleotides are a hitherto unappreciated source of PARP-trapping DNA lesions, and that the frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukaemia could provide an opportunity to exploit these findings therapeutically. Mutations in all three genes encoding ribonuclease H2 sensitize cells to poly(ADP-ribose) polymerase inhibitors by compromising ribonucleotide excision repair., Author(s): Michal Zimmermann [sup.1] , Olga Murina [sup.2] , Martin A. M. Reijns [sup.2] , Angelo Agathanggelou [sup.3] , Rachel Challis [sup.2] , Zygimante Tarnauskaite [sup.2] , Morwenna Muir [sup.4] [...]

Published
2018
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12. A novel ILK/STAT3 pathway controls plasticity in a neural stem cell model of glioblastoma

Author

Loftus, Alexander E. P., Romano, Marianna S., Phuong, Anh Nguyen, Muir, Morwenna T., Dawson, John C., Avalle, Lidia, Douglas, Adam T., Mort, Richard L., Byron, Adam, Carragher, Neil O., Pollard, Steven M., Brunton, Valerie G., Frame, Margaret C., Loftus, Alexander E. P., Romano, Marianna S., Phuong, Anh Nguyen, Muir, Morwenna T., Dawson, John C., Avalle, Lidia, Douglas, Adam T., Mort, Richard L., Byron, Adam, Carragher, Neil O., Pollard, Steven M., Brunton, Valerie G., and Frame, Margaret C.

Published
2023

15. Data from Kindlin-1 Promotes Pulmonary Breast Cancer Metastasis

Author

Sarvi, Sana, primary, Patel, Hitesh, primary, Li, Jun, primary, Dodd, Georgia L., primary, Creedon, Helen, primary, Muir, Morwenna, primary, Ward, Jocelyn, primary, Dawson, John C., primary, Lee, Martin, primary, Culley, Jayne, primary, Salter, Donald M., primary, Sims, Andrew H., primary, Byron, Adam, primary, and Brunton, Valerie G., primary

Published
2023
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16. Figure S1 from Kindlin-1 Promotes Pulmonary Breast Cancer Metastasis

Author

Sarvi, Sana, primary, Patel, Hitesh, primary, Li, Jun, primary, Dodd, Georgia L., primary, Creedon, Helen, primary, Muir, Morwenna, primary, Ward, Jocelyn, primary, Dawson, John C., primary, Lee, Martin, primary, Culley, Jayne, primary, Salter, Donald M., primary, Sims, Andrew H., primary, Byron, Adam, primary, and Brunton, Valerie G., primary

Published
2023
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17. Supplementary Data from A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability

Author

Temps, Carolin, primary, Lietha, Daniel, primary, Webb, Emily R., primary, Li, Xue-Feng, primary, Dawson, John C., primary, Muir, Morwenna, primary, Macleod, Kenneth G., primary, Valero, Teresa, primary, Munro, Alison F., primary, Contreras-Montoya, Rafael, primary, Luque-Ortega, Juan R., primary, Fraser, Craig, primary, Beetham, Henry, primary, Schoenherr, Christina, primary, Lopalco, Maria, primary, Arends, Mark J., primary, Frame, Margaret C., primary, Qian, Bin-Zhi, primary, Brunton, Valerie G., primary, Carragher, Neil O., primary, and Unciti-Broceta, Asier, primary

Published
2023
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19. Supplementary Figures S1-S4 from Trastuzumab and Pertuzumab Produce Changes in Morphology and Estrogen Receptor Signaling in Ovarian Cancer Xenografts Revealing New Treatment Strategies

Author

Faratian, Dana, primary, Zweemer, Annelien J.M., primary, Nagumo, Yoko, primary, Sims, Andrew H., primary, Muir, Morwenna, primary, Dodds, Michael, primary, Mullen, Peter, primary, Um, Inhwa, primary, Kay, Charlene, primary, Hasmann, Max, primary, Harrison, David J., primary, and Langdon, Simon P., primary

Published
2023
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21. Table S1 from Kindlin-1 Promotes Pulmonary Breast Cancer Metastasis

Author

Sarvi, Sana, primary, Patel, Hitesh, primary, Li, Jun, primary, Dodd, Georgia L., primary, Creedon, Helen, primary, Muir, Morwenna, primary, Ward, Jocelyn, primary, Dawson, John C., primary, Lee, Martin, primary, Culley, Jayne, primary, Salter, Donald M., primary, Sims, Andrew H., primary, Byron, Adam, primary, and Brunton, Valerie G., primary

Published
2023
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22. Data from Trastuzumab and Pertuzumab Produce Changes in Morphology and Estrogen Receptor Signaling in Ovarian Cancer Xenografts Revealing New Treatment Strategies

Author

Faratian, Dana, primary, Zweemer, Annelien J.M., primary, Nagumo, Yoko, primary, Sims, Andrew H., primary, Muir, Morwenna, primary, Dodds, Michael, primary, Mullen, Peter, primary, Um, Inhwa, primary, Kay, Charlene, primary, Hasmann, Max, primary, Harrison, David J., primary, and Langdon, Simon P., primary

Published
2023
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23. Data from A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability

Author

Temps, Carolin, primary, Lietha, Daniel, primary, Webb, Emily R., primary, Li, Xue-Feng, primary, Dawson, John C., primary, Muir, Morwenna, primary, Macleod, Kenneth G., primary, Valero, Teresa, primary, Munro, Alison F., primary, Contreras-Montoya, Rafael, primary, Luque-Ortega, Juan R., primary, Fraser, Craig, primary, Beetham, Henry, primary, Schoenherr, Christina, primary, Lopalco, Maria, primary, Arends, Mark J., primary, Frame, Margaret C., primary, Qian, Bin-Zhi, primary, Brunton, Valerie G., primary, Carragher, Neil O., primary, and Unciti-Broceta, Asier, primary

Published
2023
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25. Supplementary Figure 5 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Author

Gourley, Charlie, primary, Paige, Adam J.W., primary, Taylor, Karen J., primary, Ward, Carol, primary, Kuske, Barbara, primary, Zhang, Jieqing, primary, Sun, Mingjun, primary, Janczar, Szymon, primary, Harrison, David J., primary, Muir, Morwenna, primary, Smyth, John F., primary, and Gabra, Hani, primary

Published
2023
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26. Supplementary Methods, Legends for Figures 1-5 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Author

Gourley, Charlie, primary, Paige, Adam J.W., primary, Taylor, Karen J., primary, Ward, Carol, primary, Kuske, Barbara, primary, Zhang, Jieqing, primary, Sun, Mingjun, primary, Janczar, Szymon, primary, Harrison, David J., primary, Muir, Morwenna, primary, Smyth, John F., primary, and Gabra, Hani, primary

Published
2023
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27. Supplementary Figure 3 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Author

Gourley, Charlie, primary, Paige, Adam J.W., primary, Taylor, Karen J., primary, Ward, Carol, primary, Kuske, Barbara, primary, Zhang, Jieqing, primary, Sun, Mingjun, primary, Janczar, Szymon, primary, Harrison, David J., primary, Muir, Morwenna, primary, Smyth, John F., primary, and Gabra, Hani, primary

Published
2023
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28. Supplementary Figure 4 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Author

Gourley, Charlie, primary, Paige, Adam J.W., primary, Taylor, Karen J., primary, Ward, Carol, primary, Kuske, Barbara, primary, Zhang, Jieqing, primary, Sun, Mingjun, primary, Janczar, Szymon, primary, Harrison, David J., primary, Muir, Morwenna, primary, Smyth, John F., primary, and Gabra, Hani, primary

Published
2023
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29. Supplementary Figure 2 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Author

Gourley, Charlie, primary, Paige, Adam J.W., primary, Taylor, Karen J., primary, Ward, Carol, primary, Kuske, Barbara, primary, Zhang, Jieqing, primary, Sun, Mingjun, primary, Janczar, Szymon, primary, Harrison, David J., primary, Muir, Morwenna, primary, Smyth, John F., primary, and Gabra, Hani, primary

Published
2023
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31. Supplementary Figure 1 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Author

Gourley, Charlie, primary, Paige, Adam J.W., primary, Taylor, Karen J., primary, Ward, Carol, primary, Kuske, Barbara, primary, Zhang, Jieqing, primary, Sun, Mingjun, primary, Janczar, Szymon, primary, Harrison, David J., primary, Muir, Morwenna, primary, Smyth, John F., primary, and Gabra, Hani, primary

Published
2023
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32. 11β-HSD1 inhibition does not affect murine tumour angiogenesis but may exert a selective effect on tumour growth by modulating inflammation and fibrosis

Author

Davidson, Callam T., primary, Miller, Eileen, additional, Muir, Morwenna, additional, Dawson, John C., additional, Lee, Martin, additional, Aitken, Stuart, additional, Serrels, Alan, additional, Webster, Scott P., additional, Homer, Natalie Z. M., additional, Andrew, Ruth, additional, Brunton, Valerie G., additional, Hadoke, Patrick W. F., additional, and Walker, Brian R., additional

Published
2023
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35. Toll-like receptor orchestrates a tumor suppressor response in non-small cell lung cancer

Author

Millar, Fraser, Pennycuick, Adam, Muir, Morwenna, Quintanilla, Andrea, Hari, Priya, Freyer, Elisabeth, Gautier, Philippe, Meynert, Alison M, Grimes, Graeme R, Salomo Coll, Carla, Zdral, Sofia, Victorelli, Stella, Teixeira, Vitor H., Connolly, John, Passos, Joao F, Ros, Marian A, Wallace, William, Frame, Margaret C, Sims, Andrew H, Boulter, Luke, Janes, Sam M, Wilkinson, Simon, and Acosta, Juan Carlos

Abstract

Targeting early-stage lung cancer is vital to improve survival. Yet, the mechanisms and components of the early tumor suppressor response in lung cancer are not well understood. In this report we study the role of TLR2, a regulator of oncogene-induced senescence which is a key tumor suppressor response in premalignancy. Using human lung cancer samples and genetically engineered mouse models we show that TLR2 is active early in lung tumorigenesis where it correlates with improved survival and clinical regression.Mechanistically, TLR2 impairs early lung cancer progression via activation of cell intrinsic cell cycle arrest pathways and the proinflammatory senescence-associated secretory phenotype (SASP). The SASP regulates non-cell autonomous anti-tumor responses such as immune surveillance of premalignant cells, and we observe impaired myeloid cell recruitment to lung tumors following Tlr2 loss. Lastly, we show that administration of a TLR2 agonist reduces lung tumor growth, highlighting TLR2 as a possible therapeutic target.

Published
2022
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36. Toll-like receptor 2 orchestrates a tumor suppressor response in non-small cell lung cancer

Author

Millar, Fraser R., primary, Pennycuick, Adam, additional, Muir, Morwenna, additional, Quintanilla, Andrea, additional, Hari, Priya, additional, Freyer, Elisabeth, additional, Gautier, Philippe, additional, Meynert, Alison, additional, Grimes, Graeme, additional, Coll, Carla Salomo, additional, Zdral, Sofia, additional, Victorelli, Stella, additional, Teixeira, Vitor H., additional, Connelly, John, additional, Passos, João F., additional, Ros, Marian A., additional, Wallace, William A.H., additional, Frame, Margaret C., additional, Sims, Andrew H., additional, Boulter, Luke, additional, Janes, Sam M., additional, Wilkinson, Simon, additional, and Acosta, Juan Carlos, additional

Published
2022
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37. A conformation selective mode of inhibiting SRC improves drug efficacy and tolerability

Author

University of Edinburgh, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, CSIC - Centro de Investigaciones Biológicas Margarita Salas (CIB), Universidad de Granada, Wellcome Trust, Lietha, Daniel [0000-0002-6133-6486], Webb, Emily R. [0000-0001-9339-4544], Li, Xue-Feng [0000-0003-2612-0310], Muir, Morwenna [0000-0001-5835-3886], Luque-Ortega, Juan Román [0000-0003-3206-7480], Beetham, Henry [0000-0002-8446-2485], Schoenherr, Christina [0000-0002-0983-6168], Arends, Mark J. [0000-0002-6826-8770], Frame, Margaret C. [0000-0001-5882-1942], Carragher, Neil O. [0000-0001-5541-9747], Unciti-Broceta, Asier [0000-0003-1029-2855], Temps, Caroline, Lietha, Daniel, Webb, Emily R., Li, Xue-Feng, Dawson, John C., Muir, Morwenna, Macleod, Kenneth G., Valero, Teresa, Munro, Alison F., Contreras-Montoya, Rafael, Luque-Ortega, Juan Román, Fraser, Craig, Beetham, Henry, Schoenherr, Christina, Lopalco, Maria, Arends, Mark J., Frame, Margaret C., Qian, Bin-Zhi, Brunton, Valerie G., Carragher, Neil O., Unciti-Broceta, Asier, University of Edinburgh, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, CSIC - Centro de Investigaciones Biológicas Margarita Salas (CIB), Universidad de Granada, Wellcome Trust, Lietha, Daniel [0000-0002-6133-6486], Webb, Emily R. [0000-0001-9339-4544], Li, Xue-Feng [0000-0003-2612-0310], Muir, Morwenna [0000-0001-5835-3886], Luque-Ortega, Juan Román [0000-0003-3206-7480], Beetham, Henry [0000-0002-8446-2485], Schoenherr, Christina [0000-0002-0983-6168], Arends, Mark J. [0000-0002-6826-8770], Frame, Margaret C. [0000-0001-5882-1942], Carragher, Neil O. [0000-0001-5541-9747], Unciti-Broceta, Asier [0000-0003-1029-2855], Temps, Caroline, Lietha, Daniel, Webb, Emily R., Li, Xue-Feng, Dawson, John C., Muir, Morwenna, Macleod, Kenneth G., Valero, Teresa, Munro, Alison F., Contreras-Montoya, Rafael, Luque-Ortega, Juan Román, Fraser, Craig, Beetham, Henry, Schoenherr, Christina, Lopalco, Maria, Arends, Mark J., Frame, Margaret C., Qian, Bin-Zhi, Brunton, Valerie G., Carragher, Neil O., and Unciti-Broceta, Asier

Abstract

Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This unprecedented mechanism of action resulted in highly potent and selective pathway inhibition, in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this novel mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders.

Published
2021

38. Toll-like receptor 2 orchestrates a tumor suppressor response in non-small cell lung cancer

Author

Wellcome Trust, Cancer Research UK, University of Edinburgh, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), National Institute on Aging (US), Millar, Fraser R., Pennycuick, Adam, Muir, Morwenna, Quintanilla, Andrea, Hari, Priya, Freyer, lisabeth, Gautier, Philippe, Meynert, Alison, Grimes, Graeme R., Salomo Coll, Carla, Zdral, Sofía, Victorelli, Stella, Teixeira, Vitor H., Connelly, John, Passos, João F., Ros, María A., Wallace, William A.H., Frame, Margaret C., Sims, Andrew H., Boulter, Luke, Janes, Sam M., Wilkinson, Simon, Acosta, Juan C., Wellcome Trust, Cancer Research UK, University of Edinburgh, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), National Institute on Aging (US), Millar, Fraser R., Pennycuick, Adam, Muir, Morwenna, Quintanilla, Andrea, Hari, Priya, Freyer, lisabeth, Gautier, Philippe, Meynert, Alison, Grimes, Graeme R., Salomo Coll, Carla, Zdral, Sofía, Victorelli, Stella, Teixeira, Vitor H., Connelly, John, Passos, João F., Ros, María A., Wallace, William A.H., Frame, Margaret C., Sims, Andrew H., Boulter, Luke, Janes, Sam M., Wilkinson, Simon, and Acosta, Juan C.

Abstract

Targeting early-stage lung cancer is vital to improve survival. However, the mechanisms and components of the early tumor suppressor response in lung cancer are not well understood. In this report, we study the role of Toll-like receptor 2 (TLR2), a regulator of oncogene-induced senescence, which is a key tumor suppressor response in premalignancy. Using human lung cancer samples and genetically engineered mouse models, we show that TLR2 is active early in lung tumorigenesis, where it correlates with improved survival and clinical regression. Mechanistically, TLR2 impairs early lung cancer progression via activation of cell intrinsic cell cycle arrest pathways and the proinflammatory senescence-associated secretory phenotype (SASP). The SASP regulates non-cell autonomous anti-tumor responses, such as immune surveillance of premalignant cells, and we observe impaired myeloid cell recruitment to lung tumors after Tlr2 loss. Last, we show that administration of a TLR2 agonist reduces lung tumor growth, highlighting TLR2 as a possible therapeutic target.

Published
2022

39. Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence

Author

Cancer Research UK, University of Edinburgh, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), National Institutes of Health (US), Biotechnology and Biological Sciences Research Council (UK), Wellcome Trust, Medical Research Council (UK), Fernández-Duran, Irene, Quintanilla, Andrea, Tarrats, Núria, Birch, Jodie, Hari, Priya, Millar, Fraser R., Lagnado, Anthony B., Smer-Barreto, Vanessa, Muir, Morwenna, Brunton, Valerie G., Passos, João F., Acosta, Juan C., Cancer Research UK, University of Edinburgh, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), National Institutes of Health (US), Biotechnology and Biological Sciences Research Council (UK), Wellcome Trust, Medical Research Council (UK), Fernández-Duran, Irene, Quintanilla, Andrea, Tarrats, Núria, Birch, Jodie, Hari, Priya, Millar, Fraser R., Lagnado, Anthony B., Smer-Barreto, Vanessa, Muir, Morwenna, Brunton, Valerie G., Passos, João F., and Acosta, Juan C.

Abstract

Cytoplasmic recognition of microbial lipopolysaccharides (LPS) in human cells is elicited by the caspase-4 and caspase-5 noncanonical inflammasomes, which induce a form of inflammatory cell death termed pyroptosis. Here we show that LPS-mediated activation of caspase-4 also induces a stress response promoting cellular senescence, which is dependent on the caspase-4 substrate gasdermin-D and the tumor suppressor p53. Furthermore, we found that the caspase-4 noncanonical inflammasome is induced and assembled in response to oncogenic RAS signaling during oncogene-induced senescence (OIS). Moreover, targeting caspase-4 expression in OIS showed its critical role in the senescence-associated secretory phenotype and the cell cycle arrest induced in cellular senescence. Finally, we observed that caspase-4 induction occurs in vivo in mouse models of tumor suppression and ageing. Altogether, we are showing that cellular senescence is induced by cytoplasmic LPS recognition by the noncanonical inflammasome and that this pathway is conserved in the cellular response to oncogenic stress.

Published
2022

40. MYC sensitises cells to apoptosis by driving energetic demand

Author

Wellcome Trust, Cancer Research UK, Barts Charity, Medical Research Council (UK), Edwards-Hicks, Joy, Su, Huizhong, Mangolini, Maurizio, Yoneten, Kubra K., Wills, Jimi, Rodriguez-Blanco, Giovanny, Young, Christine, Cho, Kevin, Barker, Heather, Muir, Morwenna, Guerrieri, Ania Naila, Li, Xue-Feng, White, Rachel, Manasterski, Piotr, Mandrou, Elena, Wills, Karen, Chen, Jingyu, Abraham, Emily, Sateri, Kianoosh, Qian, Bin-Zhi, Bankhead, Peter, Arends, Mark, Gammoh, Noor, Kriegsheim, Alexvon, Patti, Gary J., Sim, Andrew H., Acosta, Juan C., Brunton, Valerie G., Kranc, Kamil R., Christophorou, Maria, Pearce, Erika L., Ringshausen, Ingo, Finch, Andrew J., Wellcome Trust, Cancer Research UK, Barts Charity, Medical Research Council (UK), Edwards-Hicks, Joy, Su, Huizhong, Mangolini, Maurizio, Yoneten, Kubra K., Wills, Jimi, Rodriguez-Blanco, Giovanny, Young, Christine, Cho, Kevin, Barker, Heather, Muir, Morwenna, Guerrieri, Ania Naila, Li, Xue-Feng, White, Rachel, Manasterski, Piotr, Mandrou, Elena, Wills, Karen, Chen, Jingyu, Abraham, Emily, Sateri, Kianoosh, Qian, Bin-Zhi, Bankhead, Peter, Arends, Mark, Gammoh, Noor, Kriegsheim, Alexvon, Patti, Gary J., Sim, Andrew H., Acosta, Juan C., Brunton, Valerie G., Kranc, Kamil R., Christophorou, Maria, Pearce, Erika L., Ringshausen, Ingo, and Finch, Andrew J.

Abstract

The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.

Published
2022

42. A novel mode of inhibiting SRC improves drug efficacy and tolerability

Author

Temps, Carolin, Lietha, Daniel, Webb, Emily R., Li, Xue-Feng, Dawson, John C., Muir, Morwenna, Macleod, Kenneth G., Valero, Teresa, Munro, Alison F., Contreras-Montoya, Rafael, Luque-Ortega, Juan R., Fraser, Craig, Beetham, Henry, Schoenherr, Christina, Lopalco, Maria, Arends, Mark J., Frame, Margaret C., Qian, Bin-Zhi, Brunton, Valerie G., Carragher, Neil O., and Unciti-Broceta, Asier

Subjects
Mice, Inbred BALB C, Protein Conformation, Mice, Nude, Apoptosis, Bone Neoplasms, Breast Neoplasms, Xenograft Model Antitumor Assays, Article, Small Molecule Libraries, Mice, Pyrimidines, src-Family Kinases, Piperidines, Focal Adhesion Kinase 1, Tumor Cells, Cultured, Animals, Humans, Pyrazoles, Female, Proto-Oncogene Proteins c-abl, Protein Kinase Inhibitors, Cell Proliferation
Abstract

Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This unprecedented mechanism of action resulted in highly potent and selective pathway inhibition, in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this novel mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders.

Published
2021

44. Loss of Integrin-Linked Kinase Sensitizes Breast Cancer to SRC Inhibitors

Author

Beetham, Henry, primary, Griffith, Billie G.C., additional, Murina, Olga, additional, Loftus, Alexander E.P., additional, Parry, David A., additional, Temps, Carolin, additional, Culley, Jayne, additional, Muir, Morwenna, additional, Unciti-Broceta, Asier, additional, Sims, Andrew H., additional, Byron, Adam, additional, and Brunton, Valerie G., additional

Published
2021
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45. Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence

Author

Fernández-Duran, Irene, primary, Quintanilla, Andrea, additional, Tarrats, Núria, additional, Birch, Jodie, additional, Hari, Priya, additional, Millar, Fraser R., additional, Lagnado, Anthony B., additional, Smer-Barreto, Vanessa, additional, Muir, Morwenna, additional, Brunton, Valerie G., additional, Passos, João F., additional, and Acosta, Juan Carlos, additional

Published
2021
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47. A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability

Author

Temps, Carolin, primary, Lietha, Daniel, additional, Webb, Emily R., additional, Li, Xue-Feng, additional, Dawson, John C., additional, Muir, Morwenna, additional, Macleod, Kenneth G., additional, Valero, Teresa, additional, Munro, Alison F., additional, Contreras-Montoya, Rafael, additional, Luque-Ortega, Juan R., additional, Fraser, Craig, additional, Beetham, Henry, additional, Schoenherr, Christina, additional, Lopalco, Maria, additional, Arends, Mark J., additional, Frame, Margaret C., additional, Qian, Bin-Zhi, additional, Brunton, Valerie G., additional, Carragher, Neil O., additional, and Unciti-Broceta, Asier, additional

Published
2021
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48. 11β-HSD1 inhibition does not affect murine tumour angiogenesis but may exert a selective effect on tumour growth by modulating inflammation and fibrosis

Author

Davidson, Callam T, primary, Miller, Eileen, additional, Muir, Morwenna, additional, Dawson, John C., additional, Lee, Martin, additional, Aitken, Stuart, additional, Serrels, Alan, additional, Webster, Scott P, additional, Homer, Natalie Z. M., additional, Andrew, Ruth, additional, Brunton, Valerie G., additional, Hadoke, Patrick W. F., additional, and Walker, Brian R., additional

Published
2021
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50. Toll-like receptor 2 orchestrates a potent anti-tumor response in non-small cell lung cancer

Author

Millar, Fraser R., primary, Pennycuick, Adam, additional, Muir, Morwenna, additional, Quintanella, Andrea, additional, Hari, Priya, additional, Freyer, Elisabeth, additional, Gautier, Philippe, additional, Meynert, Alison, additional, Teixeira, Vitor H., additional, Connelly, John, additional, Wallace, William AH, additional, Sims, Andrew H, additional, Frame, Margaret C., additional, Boulter, Luke, additional, Janes, Sam M., additional, Wilkinson, Simon, additional, and Acosta, Juan Carlos, additional

Published
2021
Full Text
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