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Your search keyword '"Joshua D. G. Leach"' showing total 5 results
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5 results on '"Joshua D. G. Leach"'

1. Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features

Author

Dustin J. Flanagan, Raheleh Amirkhah, David F. Vincent, Nuray Gundaz, Pauline Gentaz, Patrizia Cammareri, Aoife J. McCooey, Amy M. B. McCorry, Natalie C. Fisher, Hayley L. Davis, Rachel A. Ridgway, Jeroen Lohuis, Joshua D. G. Leach, Rene Jackstadt, Kathryn Gilroy, Elisa Mariella, Colin Nixon, William Clark, Ann Hedley, Elke K. Markert, Douglas Strathdee, Laurent Bartholin, Keara L. Redmond, Emma M. Kerr, Daniel B. Longley, Fiona Ginty, Sanghee Cho, Helen G. Coleman, Maurice B. Loughrey, Alberto Bardelli, Timothy S. Maughan, Andrew D. Campbell, Mark Lawler, Simon J. Leedham, Simon T. Barry, Gareth J. Inman, Jacco van Rheenen, Philip D. Dunne, and Owen J. Sansom

Subjects
Science
Abstract

It remains critical to identify colorectal cancers (CRC) that will disseminate as early as possible. Here, the authors identify CRC tumours that are aggressive and prone to early dissemination, characterised by epithelial TGFβ and growth-factor signalling - which could be targeted with MEK/EGFR inhibitors.

Published
2022
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2. Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Author

Joshua D. G. Leach, Nikola Vlahov, Petros Tsantoulis, Rachel A. Ridgway, Dustin J. Flanagan, Kathryn Gilroy, Nathalie Sphyris, Ester G. Vázquez, David F. Vincent, William J. Faller, Michael C. Hodder, Alexander Raven, Sigrid Fey, Arafath K. Najumudeen, Douglas Strathdee, Colin Nixon, Mark Hughes, William Clark, Robin Shaw, S:CORT consortium, Sander R. van Hooff, David J. Huels, Jan Paul Medema, Simon T. Barry, Margaret C. Frame, Asier Unciti-Broceta, Simon J. Leedham, Gareth J. Inman, Rene Jackstadt, Barry J. Thompson, Andrew D. Campbell, Sabine Tejpar, and Owen J. Sansom

Subjects
Science
Abstract

Right-sided colorectal cancer (rCRC) has a different mutational spectrum to the left-sided counterpart. Here the authors develop a mouse model of rCRC that recapitulates human BRAF-mutant rCRC and show that loss of TGFβ-receptor signalling and inflammation induce the development of colonic tumours with a foetal-like phenotype.

Published
2021
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3. Author Correction: Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features

Author

Dustin J. Flanagan, Raheleh Amirkhah, David F. Vincent, Nuray Gunduz, Pauline Gentaz, Patrizia Cammareri, Aoife J. McCooey, Amy M. B. McCorry, Natalie C. Fisher, Hayley L. Davis, Rachel A. Ridgway, Jeroen Lohuis, Joshua D. G. Leach, Rene Jackstadt, Kathryn Gilroy, Elisa Mariella, Colin Nixon, William Clark, Ann Hedley, Elke K. Markert, Douglas Strathdee, Laurent Bartholin, Keara L. Redmond, Emma M. Kerr, Daniel B. Longley, Fiona Ginty, Sanghee Cho, Helen G. Coleman, Maurice B. Loughrey, Alberto Bardelli, Timothy S. Maughan, Andrew D. Campbell, Mark Lawler, Simon J. Leedham, Simon T. Barry, Gareth J. Inman, Jacco van Rheenen, Philip D. Dunne, and Owen J. Sansom

Subjects
Science
Published
2023
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4. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer

Author

Arafath K, Najumudeen, Fatih, Ceteci, Sigrid K, Fey, Gregory, Hamm, Rory T, Steven, Holly, Hall, Chelsea J, Nikula, Alex, Dexter, Teresa, Murta, Alan M, Race, David, Sumpton, Nikola, Vlahov, David M, Gay, John R P, Knight, Rene, Jackstadt, Joshua D G, Leach, Rachel A, Ridgway, Emma R, Johnson, Colin, Nixon, Ann, Hedley, Kathryn, Gilroy, William, Clark, Sudhir B, Malla, Philip D, Dunne, Giovanny, Rodriguez-Blanco, Susan E, Critchlow, Agata, Mrowinska, Gaurav, Malviya, Dmitry, Solovyev, Gavin, Brown, David Y, Lewis, Gillian M, Mackay, Douglas, Strathdee, Saverio, Tardito, Eyal, Gottlieb, Zoltan, Takats, Simon T, Barry, Richard J A, Goodwin, Josephine, Bunch, Martin, Bushell, Andrew D, Campbell, and Harry, Hall

Subjects
Amino Acid Transport System ASC, Carcinogenesis, Glutamine, TOR Serine-Threonine Kinases, Kaplan-Meier Estimate, Oncogenes, Mechanistic Target of Rapamycin Complex 1, Large Neutral Amino Acid-Transporter 1, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Minor Histocompatibility Antigens, Proto-Oncogene Proteins p21(ras), Mutation, Animals, Humans, RNA, Messenger, Intestinal Mucosa, Neoplasm Metastasis, 5' Untranslated Regions, Colorectal Neoplasms, Cell Proliferation, Signal Transduction
Abstract

Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early- and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins the enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via inhibition of the mTORC1 regulator, together with Slc7a5 deletion abrogates the growth of established Kras-mutant tumors. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.

Published
2020

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