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1. SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response

Author

Bland, Philip, Saville, Harry, Wai, Patty T., Curnow, Lucinda, Muirhead, Gareth, Nieminuszczy, Jadwiga, Ravindran, Nivedita, John, Marie Beatrix, Hedayat, Somaieh, Barker, Holly E., Wright, James, Yu, Lu, Mavrommati, Ioanna, Read, Abigail, Peck, Barrie, Allen, Mark, Gazinska, Patrycja, Pemberton, Helen N., Gulati, Aditi, Nash, Sarah, Noor, Farzana, Guppy, Naomi, Roxanis, Ioannis, Pratt, Guy, Oldreive, Ceri, Stankovic, Tatjana, Barlow, Samantha, Kalirai, Helen, Coupland, Sarah E., Broderick, Ronan, Alsafadi, Samar, Houy, Alexandre, Stern, Marc-Henri, Pettit, Stephen, Choudhary, Jyoti S., Haider, Syed, Niedzwiedz, Wojciech, Lord, Christopher J., and Natrajan, Rachael

Published
2023
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2. A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death

Author

Mannion, Jonathan, primary, Gifford, Valentina, additional, Bellenie, Benjamin, additional, Fernando, Winnie, additional, Ramos Garcia, Laura, additional, Wilson, Rebecca, additional, John, Sidonie Wicky, additional, Udainiya, Savita, additional, Patin, Emmanuel C., additional, Tiu, Crescens, additional, Smith, Angel, additional, Goicoechea, Maria, additional, Craxton, Andrew, additional, Moraes de Vasconcelos, Nathalia, additional, Guppy, Naomi, additional, Cheung, Kwai-Ming J., additional, Cundy, Nicholas J., additional, Pierrat, Olivier, additional, Brennan, Alfie, additional, Roumeliotis, Theodoros I., additional, Benstead-Hume, Graeme, additional, Alexander, John, additional, Muirhead, Gareth, additional, Layzell, Scott, additional, Lyu, Wenxin, additional, Roulstone, Victoria, additional, Allen, Mark, additional, Baldock, Holly, additional, Legrand, Arnaud, additional, Gabel, Florian, additional, Serrano-Aparicio, Natalia, additional, Starling, Chris, additional, Guo, Hongyan, additional, Upton, Jason, additional, Gyrd-Hansen, Mads, additional, MacFarlane, Marion, additional, Seddon, Benedict, additional, Raynaud, Florence, additional, Roxanis, Ioannis, additional, Harrington, Kevin, additional, Haider, Syed, additional, Choudhary, Jyoti S., additional, Hoelder, Swen, additional, Tenev, Tencho, additional, and Meier, Pascal, additional

Published
2024
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3. Analysis of the microbiome and host-transcriptome in psoriasis and atopic dermatitis

Author

Muirhead, Gareth Sion, Tsoka, Sophia, and Nestle, Frank Oliver

Subjects
004
Abstract

Skin is the primary interface to the external environment, protecting us from harmful compounds and infection. Over many millennia, coevolution has culminated in a mutualistic relationship between ourselves and a specialised, yet diverse resident community of microorganisms. This microbiota is thought to exist in a delicate balance to maintain homeostatic equilibrium, and plays a role in the shaping of our immune system. Skin diseases are some of the most common human disorders and present a considerable economic burden. There is now growing appreciation of the role the cutaneous microbiome plays in disease, and how host-microbe interplay is associated with disorders of the immune system. The cutaneous microbiota as well as the host transcriptome and the interactions between them is the focus of this thesis. Computational methods were used to examine the microbiota and transcriptomes of a large cohort of matched samples from healthy volunteers and patients with Atopic Dermatitis (AD) and Psoriasis (PSO). The community composition of inflamed and healthy skin was assessed and the specific species which are over-represented on diseased skin were identified. In parallel, the host gene expression was pro led to identify common and disease specific transcriptional signatures revealing clinically relevant pathways. Next, using schemes of dimensionality reduction and computational methods, the associations between microbes, disease severity and host transcription was interrogated. Staphylococcus aureus demonstrated an impressive relationship with AD associated gene signatures, whereas host-microbe associations in PSO were inconclusive. Using Weighted Gene Co-expression Networks Analysis (WGCNA), gene-gene interaction networks were reconstructed and differentially connected modules between healthy and inflammatory states were identified. Modules encoding processes for the epidermal barrier, extracellular matrix, non-coding RNA metabolism and immune system processes were all associated with the relative abundance of S. aureus. Overall, whilst associations in psoriasis were inconclusive, a range of host-microbe interactions were uncovered in AD. The results presented in this thesis contribute towards a greater understanding of the differences in the cutaneous microbiome and the transcriptional mechanisms which underlie allergic and autoimmune inflammation.

Published
2017

5. PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer

Author

Chabanon, Roman M., Muirhead, Gareth, Krastev, Dragomir B., Adam, Julien, Morel, Daphne, Garrido, Marlene, Lamb, Andrew, Henon, Clemence, Dorvault, Nicolas, Rouanne, Mathieu, Marlow, Rebecca, Bajrami, Ilirjana, Cardenosa, Marta Llorca, Konde, Asha, Besse, Benjamin, Ashworth, Alan, Haider, Stephen J. PettiSyed, Marabelle, Aurelien, Soria, Andrew N.J. TuJean-Charles, Lord, Christopher J., and Postel-Vinay, Sophie

Subjects
Gene expression -- Research, Cellular immunity -- Research, Enzyme inhibitors -- Dosage and administration, Non-small cell lung cancer -- Genetic aspects -- Drug therapy -- Research, Cancer genetics, Gene mutation, Tumors, BRCA mutations, Small cell lung cancer, DNA repair, DNA, Chromatin, Breast cancer, Lung cancer, Immune response, Cancer cells, Genes, Monosaccharides, Health care industry
Abstract

The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN- [gamma]-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1- deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations., Introduction Immune checkpoint inhibitors (ICIs) have revolutionized the prognosis of several aggressive cancers, notably non-small cell lung cancer (NSCLC). Recent impressive results of large phase III trials in NSCLC have [...]

Published
2019
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7. Microbe-host interplay in atopic dermatitis and psoriasis

Author

Fyhrquist, Nanna, Muirhead, Gareth, Prast-Nielsen, Stefanie, Jeanmougin, Marine, Olah, Peter, Skoog, Tiina, Jules-Clement, Gerome, Feld, Micha, Barrientos-Somarribas, Mauricio, Sinkko, Hanna, van den Bogaard, Ellen H., Zeeuwen, Patrick L.J.M., Rikken, Gijs, Schalkwijk, Joost, Niehues, Hanna, Däubener, Walter, Eller, Silvia Kathrin, Alexander, Helen, Pennino, Davide, Suomela, Sari, Tessas, Ioannis, Lybeck, Emilia, Baran, Anna M., Darban, Hamid, Gangwar, Roopesh Singh, Gerstel, Ulrich, Jahn, Katharina, Karisola, Piia, Yan, Lee, Hansmann, Britta, Katayama, Shintaro, Meller, Stephan, Bylesjö, Max, Hupé, Philippe, Levi-Schaffer, Francesca, Greco, Dario, Ranki, Annamari, Schröder, Jens M., Barker, Jonathan, Kere, Juha, Tsoka, Sophia, Lauerma, Antti, Soumelis, Vassili, Nestle, Frank O., Homey, Bernhard, Andersson, Björn, and Alenius, Harri

Published
2019
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8. Table S4 from 3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer

Author

Peck, Barrie, primary, Bland, Philip, primary, Mavrommati, Ioanna, primary, Muirhead, Gareth, primary, Cottom, Hannah, primary, Wai, Patty T., primary, Maguire, Sarah L., primary, Barker, Holly E., primary, Morrison, Eamonn, primary, Kriplani, Divya, primary, Yu, Lu, primary, Gibson, Amy, primary, Falgari, Giulia, primary, Brennan, Keith, primary, Farnie, Gillian, primary, Buus, Richard, primary, Marlow, Rebecca, primary, Novo, Daniela, primary, Knight, Eleanor, primary, Guppy, Naomi, primary, Kolarevic, Daniela, primary, Susnjar, Snezana, primary, Milijic, Natasa Medic, primary, Naidoo, Kalnisha, primary, Gazinska, Patrycja, primary, Roxanis, Ioannis, primary, Pancholi, Sunil, primary, Martin, Lesley-Ann, primary, Holgersen, Erle M., primary, Cheang, Maggie C.U., primary, Noor, Farzana, primary, Postel-Vinay, Sophie, primary, Quinn, Gerard, primary, McDade, Simon, primary, Krasny, Lukas, primary, Huang, Paul, primary, Daley, Frances, primary, Wallberg, Fredrik, primary, Choudhary, Jyoti S., primary, Haider, Syed, primary, Tutt, Andrew N., primary, and Natrajan, Rachael, primary

Published
2023
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9. Supplementary Table S1 from Anti-Folate Receptor-α IgE but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling

Author

Josephs, Debra H., primary, Bax, Heather J., primary, Dodev, Tihomir, primary, Georgouli, Mirella, primary, Nakamura, Mano, primary, Pellizzari, Giulia, primary, Saul, Louise, primary, Karagiannis, Panagiotis, primary, Cheung, Anthony, primary, Herraiz, Cecilia, primary, Ilieva, Kristina M., primary, Correa, Isabel, primary, Fittall, Matthew, primary, Crescioli, Silvia, primary, Gazinska, Patrycja, primary, Woodman, Natalie, primary, Mele, Silvia, primary, Chiaruttini, Giulia, primary, Gilbert, Amy E., primary, Koers, Alexander, primary, Bracher, Marguerite, primary, Selkirk, Christopher, primary, Lentfer, Heike, primary, Barton, Claire, primary, Lever, Elliott, primary, Muirhead, Gareth, primary, Tsoka, Sophia, primary, Canevari, Silvana, primary, Figini, Mariangela, primary, Montes, Ana, primary, Downes, Noel, primary, Dombrowicz, David, primary, Corrigan, Christopher J., primary, Beavil, Andrew J., primary, Nestle, Frank O., primary, Jones, Paul S., primary, Gould, Hannah J., primary, Sanz-Moreno, Victoria, primary, Blower, Philip J., primary, Spicer, James F., primary, and Karagiannis, Sophia N., primary

Published
2023
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10. Data from Anti-Folate Receptor-α IgE but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling

Author

Josephs, Debra H., primary, Bax, Heather J., primary, Dodev, Tihomir, primary, Georgouli, Mirella, primary, Nakamura, Mano, primary, Pellizzari, Giulia, primary, Saul, Louise, primary, Karagiannis, Panagiotis, primary, Cheung, Anthony, primary, Herraiz, Cecilia, primary, Ilieva, Kristina M., primary, Correa, Isabel, primary, Fittall, Matthew, primary, Crescioli, Silvia, primary, Gazinska, Patrycja, primary, Woodman, Natalie, primary, Mele, Silvia, primary, Chiaruttini, Giulia, primary, Gilbert, Amy E., primary, Koers, Alexander, primary, Bracher, Marguerite, primary, Selkirk, Christopher, primary, Lentfer, Heike, primary, Barton, Claire, primary, Lever, Elliott, primary, Muirhead, Gareth, primary, Tsoka, Sophia, primary, Canevari, Silvana, primary, Figini, Mariangela, primary, Montes, Ana, primary, Downes, Noel, primary, Dombrowicz, David, primary, Corrigan, Christopher J., primary, Beavil, Andrew J., primary, Nestle, Frank O., primary, Jones, Paul S., primary, Gould, Hannah J., primary, Sanz-Moreno, Victoria, primary, Blower, Philip J., primary, Spicer, James F., primary, and Karagiannis, Sophia N., primary

Published
2023
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11. Data from 3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer

Author

Peck, Barrie, primary, Bland, Philip, primary, Mavrommati, Ioanna, primary, Muirhead, Gareth, primary, Cottom, Hannah, primary, Wai, Patty T., primary, Maguire, Sarah L., primary, Barker, Holly E., primary, Morrison, Eamonn, primary, Kriplani, Divya, primary, Yu, Lu, primary, Gibson, Amy, primary, Falgari, Giulia, primary, Brennan, Keith, primary, Farnie, Gillian, primary, Buus, Richard, primary, Marlow, Rebecca, primary, Novo, Daniela, primary, Knight, Eleanor, primary, Guppy, Naomi, primary, Kolarevic, Daniela, primary, Susnjar, Snezana, primary, Milijic, Natasa Medic, primary, Naidoo, Kalnisha, primary, Gazinska, Patrycja, primary, Roxanis, Ioannis, primary, Pancholi, Sunil, primary, Martin, Lesley-Ann, primary, Holgersen, Erle M., primary, Cheang, Maggie C.U., primary, Noor, Farzana, primary, Postel-Vinay, Sophie, primary, Quinn, Gerard, primary, McDade, Simon, primary, Krasny, Lukas, primary, Huang, Paul, primary, Daley, Frances, primary, Wallberg, Fredrik, primary, Choudhary, Jyoti S., primary, Haider, Syed, primary, Tutt, Andrew N., primary, and Natrajan, Rachael, primary

Published
2023
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12. Supplementary Materials and Methods from Anti-Folate Receptor-α IgE but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling

Author

Josephs, Debra H., primary, Bax, Heather J., primary, Dodev, Tihomir, primary, Georgouli, Mirella, primary, Nakamura, Mano, primary, Pellizzari, Giulia, primary, Saul, Louise, primary, Karagiannis, Panagiotis, primary, Cheung, Anthony, primary, Herraiz, Cecilia, primary, Ilieva, Kristina M., primary, Correa, Isabel, primary, Fittall, Matthew, primary, Crescioli, Silvia, primary, Gazinska, Patrycja, primary, Woodman, Natalie, primary, Mele, Silvia, primary, Chiaruttini, Giulia, primary, Gilbert, Amy E., primary, Koers, Alexander, primary, Bracher, Marguerite, primary, Selkirk, Christopher, primary, Lentfer, Heike, primary, Barton, Claire, primary, Lever, Elliott, primary, Muirhead, Gareth, primary, Tsoka, Sophia, primary, Canevari, Silvana, primary, Figini, Mariangela, primary, Montes, Ana, primary, Downes, Noel, primary, Dombrowicz, David, primary, Corrigan, Christopher J., primary, Beavil, Andrew J., primary, Nestle, Frank O., primary, Jones, Paul S., primary, Gould, Hannah J., primary, Sanz-Moreno, Victoria, primary, Blower, Philip J., primary, Spicer, James F., primary, and Karagiannis, Sophia N., primary

Published
2023
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13. Supplementary Figure Legends from Anti-Folate Receptor-α IgE but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling

Author

Josephs, Debra H., primary, Bax, Heather J., primary, Dodev, Tihomir, primary, Georgouli, Mirella, primary, Nakamura, Mano, primary, Pellizzari, Giulia, primary, Saul, Louise, primary, Karagiannis, Panagiotis, primary, Cheung, Anthony, primary, Herraiz, Cecilia, primary, Ilieva, Kristina M., primary, Correa, Isabel, primary, Fittall, Matthew, primary, Crescioli, Silvia, primary, Gazinska, Patrycja, primary, Woodman, Natalie, primary, Mele, Silvia, primary, Chiaruttini, Giulia, primary, Gilbert, Amy E., primary, Koers, Alexander, primary, Bracher, Marguerite, primary, Selkirk, Christopher, primary, Lentfer, Heike, primary, Barton, Claire, primary, Lever, Elliott, primary, Muirhead, Gareth, primary, Tsoka, Sophia, primary, Canevari, Silvana, primary, Figini, Mariangela, primary, Montes, Ana, primary, Downes, Noel, primary, Dombrowicz, David, primary, Corrigan, Christopher J., primary, Beavil, Andrew J., primary, Nestle, Frank O., primary, Jones, Paul S., primary, Gould, Hannah J., primary, Sanz-Moreno, Victoria, primary, Blower, Philip J., primary, Spicer, James F., primary, and Karagiannis, Sophia N., primary

Published
2023
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14. Supplementary Figure S1 from Anti-Folate Receptor-α IgE but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling

Author

Josephs, Debra H., primary, Bax, Heather J., primary, Dodev, Tihomir, primary, Georgouli, Mirella, primary, Nakamura, Mano, primary, Pellizzari, Giulia, primary, Saul, Louise, primary, Karagiannis, Panagiotis, primary, Cheung, Anthony, primary, Herraiz, Cecilia, primary, Ilieva, Kristina M., primary, Correa, Isabel, primary, Fittall, Matthew, primary, Crescioli, Silvia, primary, Gazinska, Patrycja, primary, Woodman, Natalie, primary, Mele, Silvia, primary, Chiaruttini, Giulia, primary, Gilbert, Amy E., primary, Koers, Alexander, primary, Bracher, Marguerite, primary, Selkirk, Christopher, primary, Lentfer, Heike, primary, Barton, Claire, primary, Lever, Elliott, primary, Muirhead, Gareth, primary, Tsoka, Sophia, primary, Canevari, Silvana, primary, Figini, Mariangela, primary, Montes, Ana, primary, Downes, Noel, primary, Dombrowicz, David, primary, Corrigan, Christopher J., primary, Beavil, Andrew J., primary, Nestle, Frank O., primary, Jones, Paul S., primary, Gould, Hannah J., primary, Sanz-Moreno, Victoria, primary, Blower, Philip J., primary, Spicer, James F., primary, and Karagiannis, Sophia N., primary

Published
2023
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15. Supplementary Methods from 3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer

Author

Peck, Barrie, primary, Bland, Philip, primary, Mavrommati, Ioanna, primary, Muirhead, Gareth, primary, Cottom, Hannah, primary, Wai, Patty T., primary, Maguire, Sarah L., primary, Barker, Holly E., primary, Morrison, Eamonn, primary, Kriplani, Divya, primary, Yu, Lu, primary, Gibson, Amy, primary, Falgari, Giulia, primary, Brennan, Keith, primary, Farnie, Gillian, primary, Buus, Richard, primary, Marlow, Rebecca, primary, Novo, Daniela, primary, Knight, Eleanor, primary, Guppy, Naomi, primary, Kolarevic, Daniela, primary, Susnjar, Snezana, primary, Milijic, Natasa Medic, primary, Naidoo, Kalnisha, primary, Gazinska, Patrycja, primary, Roxanis, Ioannis, primary, Pancholi, Sunil, primary, Martin, Lesley-Ann, primary, Holgersen, Erle M., primary, Cheang, Maggie C.U., primary, Noor, Farzana, primary, Postel-Vinay, Sophie, primary, Quinn, Gerard, primary, McDade, Simon, primary, Krasny, Lukas, primary, Huang, Paul, primary, Daley, Frances, primary, Wallberg, Fredrik, primary, Choudhary, Jyoti S., primary, Haider, Syed, primary, Tutt, Andrew N., primary, and Natrajan, Rachael, primary

Published
2023
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16. Figure S1- S8 from 3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer

Author

Peck, Barrie, primary, Bland, Philip, primary, Mavrommati, Ioanna, primary, Muirhead, Gareth, primary, Cottom, Hannah, primary, Wai, Patty T., primary, Maguire, Sarah L., primary, Barker, Holly E., primary, Morrison, Eamonn, primary, Kriplani, Divya, primary, Yu, Lu, primary, Gibson, Amy, primary, Falgari, Giulia, primary, Brennan, Keith, primary, Farnie, Gillian, primary, Buus, Richard, primary, Marlow, Rebecca, primary, Novo, Daniela, primary, Knight, Eleanor, primary, Guppy, Naomi, primary, Kolarevic, Daniela, primary, Susnjar, Snezana, primary, Milijic, Natasa Medic, primary, Naidoo, Kalnisha, primary, Gazinska, Patrycja, primary, Roxanis, Ioannis, primary, Pancholi, Sunil, primary, Martin, Lesley-Ann, primary, Holgersen, Erle M., primary, Cheang, Maggie C.U., primary, Noor, Farzana, primary, Postel-Vinay, Sophie, primary, Quinn, Gerard, primary, McDade, Simon, primary, Krasny, Lukas, primary, Huang, Paul, primary, Daley, Frances, primary, Wallberg, Fredrik, primary, Choudhary, Jyoti S., primary, Haider, Syed, primary, Tutt, Andrew N., primary, and Natrajan, Rachael, primary

Published
2023
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17. Abstract P6-10-05: Mutations in the RNA Splicing Factor SF3B1 drive endocrine therapy resistance and confer a targetable replication stress response defect through PARP inhibition

Author

Bland, Phil, primary, Saville, Harry, additional, Read, Abigail, additional, Wai, Patty, additional, Muirhead, Gareth, additional, Curnow, Lucinda, additional, Nieminuszczy, Jadwiga, additional, Ravindran, Nivedita, additional, John, Marie, additional, Hedayat, Somaieh, additional, Barker, Holly, additional, Wright, James, additional, Yu, Lu, additional, Mavrommati, Ioanna, additional, Peck, Barrie, additional, Allen, Mark, additional, Gazinska, Patrycja, additional, Pemberton, Helen, additional, Gulati, Aditi, additional, Nash, Sarah, additional, Noor, Farzana, additional, Guppy, Naomi, additional, Roxanis, Ioannis, additional, Barlow, Samantha, additional, Kalirai, Helen, additional, Coupland, Sarah, additional, Broderick, Ronan, additional, Alsafadi, Samar, additional, Houy, Alexandre, additional, Stern, Marc-Henri, additional, Pettit, Stephen, additional, Choudhary, Jyoti, additional, Haider, Syed, additional, Niedzwiedz, Wojciech, additional, Lord, Christopher, additional, and Natrajan, Rachael, additional

Published
2023
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18. 3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer

Author

Peck, Barrie, primary, Bland, Philip, additional, Mavrommati, Ioanna, additional, Muirhead, Gareth, additional, Cottom, Hannah, additional, Wai, Patty T., additional, Maguire, Sarah L., additional, Barker, Holly E., additional, Morrison, Eamonn, additional, Kriplani, Divya, additional, Yu, Lu, additional, Gibson, Amy, additional, Falgari, Giulia, additional, Brennan, Keith, additional, Farnie, Gillian, additional, Buus, Richard, additional, Marlow, Rebecca, additional, Novo, Daniela, additional, Knight, Eleanor, additional, Guppy, Naomi, additional, Kolarevic, Daniela, additional, Susnjar, Snezana, additional, Milijic, Natasa Medic, additional, Naidoo, Kalnisha, additional, Gazinska, Patrycja, additional, Roxanis, Ioannis, additional, Pancholi, Sunil, additional, Martin, Lesley-Ann, additional, Holgersen, Erle M., additional, Cheang, Maggie C.U., additional, Noor, Farzana, additional, Postel-Vinay, Sophie, additional, Quinn, Gerard, additional, McDade, Simon, additional, Krasny, Lukas, additional, Huang, Paul, additional, Daley, Frances, additional, Wallberg, Fredrik, additional, Choudhary, Jyoti S., additional, Haider, Syed, additional, Tutt, Andrew N., additional, and Natrajan, Rachael, additional

Published
2021
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19. SF3B1hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response

Author

Bland, Philip, Saville, Harry, Wai, Patty T., Curnow, Lucinda, Muirhead, Gareth, Nieminuszczy, Jadwiga, Ravindran, Nivedita, John, Marie Beatrix, Hedayat, Somaieh, Barker, Holly E., Wright, James, Yu, Lu, Mavrommati, Ioanna, Read, Abigail, Peck, Barrie, Allen, Mark, Gazinska, Patrycja, Pemberton, Helen N., Gulati, Aditi, Nash, Sarah, Noor, Farzana, Guppy, Naomi, Roxanis, Ioannis, Pratt, Guy, Oldreive, Ceri, Stankovic, Tatjana, Barlow, Samantha, Kalirai, Helen, Coupland, Sarah E., Broderick, Ronan, Alsafadi, Samar, Houy, Alexandre, Stern, Marc-Henri, Pettit, Stephen, Choudhary, Jyoti S., Haider, Syed, Niedzwiedz, Wojciech, Lord, Christopher J., and Natrajan, Rachael

Abstract

SF3B1hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUTcells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUTcancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population.

Published
2023
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22. Combining BRAF inhibition with oncolytic herpes simplex virus enhances the immune-mediated antitumor therapy of BRAF-mutant thyroid cancer

Author

Crespo-Rodriguez, Eva, primary, Bergerhoff, Katharina, additional, Bozhanova, Galabina, additional, Foo, Shane, additional, Patin, Emmanuel C, additional, Whittock, Harriet, additional, Buus, Richard, additional, Haider, Syed, additional, Muirhead, Gareth, additional, Thway, Khin, additional, Newbold, Kate, additional, Coffin, Robert S, additional, Vile, Richard G, additional, Kim, Dae, additional, McLaughlin, Martin, additional, Melcher, Alan A, additional, Harrington, Kevin J, additional, and Pedersen, Malin, additional

Published
2020
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23. An immunologically relevant rodent model demonstrates safety of therapy using a tumour-specific IgE

Author

Josephs, Debra H, Nakamura, Mano, Bax, Heather J, Dodev, Tihomir S, Muirhead, Gareth, Saul, Louise, Karagiannis, Panagiotis, Ilieva, Kristina M, Crescioli, Silvia, Gazinska, Patrycja, Woodman, Natalie, Lomardelli, Cristina, Kareemaghay, Sedigeh, Selkirk, Christopher, Lentfer, Heike, Barton, Claire, Canevari, Silvana, Figini, Mariangela, Downes, Noel, Dombrowicz, David, Corrigan, Christopher J, Nestle, Frank O, Jones, Paul S, Gould, Hannah J, Blower, Philip J, Tsoka, Sophia, Spicer, James F, and Karagiannis, Sophia N

Abstract

BACKGROUND: Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for studies on IgE antibodies represents a major impediment to their clinical translation, especially with respect to class-specific immunological functions and safety. Fcε receptor expression and structure are different in humans and mice, so that the murine system is not informative when studying human IgE biology. By contrast, FcεRI expression and cellular distribution in rats mirrors that of humans.METHODS: We are developing MOv18 IgE, a human chimeric antibody recognizing the tumour-associated antigen folate receptor alpha. We created an immunologically congruent surrogate rat model likely to recapitulate human IgE-FcεR interactions, and engineered a surrogate rat IgE equivalent to MOv18. Employing this model, we examined in vivo safety and efficacy of anti-tumour IgE antibodies.RESULTS: In immunocompetent rats, rodent IgE restricted growth of syngeneic tumours in the absence of clinical, histopathological or metabolic signs associated with obvious toxicity. No physiological or immunological evidence of a 'cytokine-storm' or allergic response was seen, even at 50 mg/kg weekly doses. IgE treatment was associated with elevated serum concentrations of TNFα, a mediator previously linked with IgE-mediated anti-tumour and anti-parasitic functions, alongside evidence of substantially elevated tumoural immune cell infiltration and immunological pathway activation in tumour-bearing lungs.CONCLUSION: Our findings indicate safety of MOv18 IgE, in conjunction with efficacy and immune activation, supporting the translation of this therapeutic approach to the clinical arena. This article is protected by copyright. All rights reserved.

Published
2018
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24. Abstract 788: Modeling tumor microenvironmental heterogeneity identifies CREBBP as a novel tumor suppressor in breast cancer

Author

Peck, Barrie, primary, Bland, Philip J., additional, Wai, Patty T., additional, Cottom, Hannah, additional, Maguire, Sarah L., additional, Morrison, Eamonn, additional, Barker, Holly E., additional, Kriplani, Divya, additional, Marlow, Rebecca, additional, Naidoo, Kalnisha, additional, Muirhead, Gareth, additional, Haider, Syed, additional, Daley, Frances, additional, Wallberg, Frederik, additional, Tutt, Andrew N., additional, and Natrajan, Rachael C., additional

Published
2018
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25. Anti-Folate Receptor-α IgE but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling

Author

Josephs, Debra H., primary, Bax, Heather J., additional, Dodev, Tihomir, additional, Georgouli, Mirella, additional, Nakamura, Mano, additional, Pellizzari, Giulia, additional, Saul, Louise, additional, Karagiannis, Panagiotis, additional, Cheung, Anthony, additional, Herraiz, Cecilia, additional, Ilieva, Kristina M., additional, Correa, Isabel, additional, Fittall, Matthew, additional, Crescioli, Silvia, additional, Gazinska, Patrycja, additional, Woodman, Natalie, additional, Mele, Silvia, additional, Chiaruttini, Giulia, additional, Gilbert, Amy E., additional, Koers, Alexander, additional, Bracher, Marguerite, additional, Selkirk, Christopher, additional, Lentfer, Heike, additional, Barton, Claire, additional, Lever, Elliott, additional, Muirhead, Gareth, additional, Tsoka, Sophia, additional, Canevari, Silvana, additional, Figini, Mariangela, additional, Montes, Ana, additional, Downes, Noel, additional, Dombrowicz, David, additional, Corrigan, Christopher J., additional, Beavil, Andrew J., additional, Nestle, Frank O., additional, Jones, Paul S., additional, Gould, Hannah J., additional, Sanz-Moreno, Victoria, additional, Blower, Philip J., additional, Spicer, James F., additional, and Karagiannis, Sophia N., additional

Published
2017
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27. Microbe-host interplay in atopic dermatitis and psoriasis

Author

Fyhrquist, Nanna, Andersson, Bjorn, Kere, Juha, Muirhead, Gareth, Stefanie Prast-Nielsen, Jeanmougin, Marine, Barker, Jonathan, Lauerma, Antti, Homey, Bernhard, Schroeder, Jens, Soumelis, Vassili, Nestle, Frank, and Alenius, Harri

28. The PRINTS database: a fine-grained protein sequence annotation and analysis resource—its status in 2012.

Author

Attwood, Teresa K., Coletta, Alain, Muirhead, Gareth, Pavlopoulou, Athanasia, Philippou, Peter B., Popov, Ivan, Romá-Mateo, Carlos, Theodosiou, Athina, and Mitchell, Alex L.

Subjects
DERMATOGLYPHICS, HUMAN fingerprints, MEMBRANE proteins, PROTEINS, BIOLOGICAL databases
Abstract

The PRINTS database, now in its 21st year, houses a collection of diagnostic protein family ‘fingerprints’. Fingerprints are groups of conserved motifs, evident in multiple sequence alignments, whose unique inter-relationships provide distinctive signatures for particular protein families and structural/functional domains. As such, they may be used to assign uncharacterized sequences to known families, and hence to infer tentative functional, structural and/or evolutionary relationships. The February 2012 release (version 42.0) includes 2156 fingerprints, encoding 12 444 individual motifs, covering a range of globular and membrane proteins, modular polypeptides and so on. Here, we report the current status of the database, and introduce a number of recent developments that help both to render a variety of our annotation and analysis tools easier to use and to make them more widely available.Database URL: www.bioinf.manchester.ac.uk/dbbrowser/PRINTS/ [ABSTRACT FROM AUTHOR]

Published
2012
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29. The PRINTS database: a fine-grained protein sequence annotation and analysis resource--its status in 2012.

Author

Attwood TK, Coletta A, Muirhead G, Pavlopoulou A, Philippou PB, Popov I, Romá-Mateo C, Theodosiou A, and Mitchell AL

Subjects
Amino Acid Motifs, Amino Acid Sequence, Conserved Sequence, Humans, Sequence Alignment, User-Computer Interface, Databases, Protein, Molecular Sequence Annotation, Proteins chemistry, Proteins genetics
Abstract

The PRINTS database, now in its 21st year, houses a collection of diagnostic protein family 'fingerprints'. Fingerprints are groups of conserved motifs, evident in multiple sequence alignments, whose unique inter-relationships provide distinctive signatures for particular protein families and structural/functional domains. As such, they may be used to assign uncharacterized sequences to known families, and hence to infer tentative functional, structural and/or evolutionary relationships. The February 2012 release (version 42.0) includes 2156 fingerprints, encoding 12 444 individual motifs, covering a range of globular and membrane proteins, modular polypeptides and so on. Here, we report the current status of the database, and introduce a number of recent developments that help both to render a variety of our annotation and analysis tools easier to use and to make them more widely available. Database URL: www.bioinf.manchester.ac.uk/dbbrowser/PRINTS/.

Published
2012
Full Text
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