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2. The αvβ6 integrin specific virotherapy, Ad5NULL-A20.FCU1, selectively delivers potent "in-tumour" chemotherapy to pancreatic ductal adenocarcinoma.

Author

Badder, Luned M., Davies, James A., Meniel, Valerie S., Marušková, Mahulena, Salvador-Barbero, Beatriz, Bayliss, Rebecca J., Phesse, Toby J., Hogan, Catherine, and Parker, Alan L.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) represent an unmet clinical need. Approximately 90% of PDACs express high levels of αvβ6 integrin. We have previously described Ad5NULL-A20, an adenovirus vector with ablated native means of cell entry and retargeted to αvβ6 integrin by incorporation of an A20 peptide. Methods: Here, we incorporate suicide genes FCY1 and FCU1 encoding for cytosine deaminase (CDase) or a combination of CDase and UPRTase, capable of catalysing a non-toxic prodrug, 5-FC into the chemotherapeutic 5-FU and downstream metabolites, into replication-deficient Ad5 and Ad5NULL-A20. Results: We show that Ad5NULL-A20 enables the transfer of suicide genes to αvβ6 integrin-positive PDAC cells which, in combination with 5-FC, results in cell death in vitro which is further mediated by a bystander effect in non-transduced cells. Intratumoural delivery of Ad5NULL-A20.FCU1 in combination with intraperitoneal delivery of 5-FC further results in tumour growth inhibition in a cell line xenograft in vivo. Using clinically-relevant 3D organoid models, we show selective transduction and therapeutic efficacy of FCU1 transgenes in combination with 5-FC. Conclusion: Taken together these data provide the preclinical rationale for combined Ad5NULL-A20.FCU1 plus 5-FC as a promising targeted therapy to mediate "in-tumour chemotherapy" and merits further investigation for the treatment of PDAC patients. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Development and Characterisation of a New Patient-Derived Xenograft Model of AR-Negative Metastatic Castration-Resistant Prostate Cancer

Author

Turnham, Daniel J., primary, Mullen, Manisha S., additional, Bullock, Nicholas P., additional, Gilroy, Kathryn L., additional, Richards, Anna E., additional, Patel, Radhika, additional, Quintela, Marcos, additional, Meniel, Valerie S., additional, Seaton, Gillian, additional, Kynaston, Howard, additional, Clarkson, Richard W. E., additional, Phesse, Toby J., additional, Nelson, Peter S., additional, Haffner, Michael C., additional, Staffurth, John N., additional, and Pearson, Helen B., additional

Published
2024
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4. Mesenchymal Niche-Derived Neuregulin-1 Drives Intestinal Stem Cell Proliferation and Regeneration of Damaged Epithelium

Author

Jardé, Thierry, Chan, Wing Hei, Rossello, Fernando J., Kaur Kahlon, Tanvir, Theocharous, Mandy, Kurian Arackal, Teni, Flores, Tracey, Giraud, Mégane, Richards, Elizabeth, Chan, Eva, Kerr, Genevieve, Engel, Rebekah M., Prasko, Mirsada, Donoghue, Jacqueline F., Abe, Shin-ichi, Phesse, Toby J., Nefzger, Christian M., McMurrick, Paul J., Powell, David R., Daly, Roger J., Polo, Jose M., and Abud, Helen E.

Published
2020
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6. Supplemetary Material and Tables from Identification of Pik3ca Mutation as a Genetic Driver of Prostate Cancer That Cooperates with Pten Loss to Accelerate Progression and Castration-Resistant Growth

Author

Pearson, Helen B., primary, Li, Jason, primary, Meniel, Valerie S., primary, Fennell, Christina M., primary, Waring, Paul, primary, Montgomery, Karen G., primary, Rebello, Richard J., primary, Macpherson, Arthi A., primary, Koushyar, Sarah, primary, Furic, Luc, primary, Cullinane, Carleen, primary, Clarkson, Richard W., primary, Smalley, Matthew J., primary, Simpson, Kaylene J., primary, Phesse, Toby J., primary, Shepherd, Peter R., primary, Humbert, Patrick O., primary, Sansom, Owen J., primary, and Phillips, Wayne A., primary

Published
2023
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7. Data from Identification of Pik3ca Mutation as a Genetic Driver of Prostate Cancer That Cooperates with Pten Loss to Accelerate Progression and Castration-Resistant Growth

Author

Pearson, Helen B., primary, Li, Jason, primary, Meniel, Valerie S., primary, Fennell, Christina M., primary, Waring, Paul, primary, Montgomery, Karen G., primary, Rebello, Richard J., primary, Macpherson, Arthi A., primary, Koushyar, Sarah, primary, Furic, Luc, primary, Cullinane, Carleen, primary, Clarkson, Richard W., primary, Smalley, Matthew J., primary, Simpson, Kaylene J., primary, Phesse, Toby J., primary, Shepherd, Peter R., primary, Humbert, Patrick O., primary, Sansom, Owen J., primary, and Phillips, Wayne A., primary

Published
2023
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8. Figure S2 from Identification of Pik3ca Mutation as a Genetic Driver of Prostate Cancer That Cooperates with Pten Loss to Accelerate Progression and Castration-Resistant Growth

Author

Pearson, Helen B., primary, Li, Jason, primary, Meniel, Valerie S., primary, Fennell, Christina M., primary, Waring, Paul, primary, Montgomery, Karen G., primary, Rebello, Richard J., primary, Macpherson, Arthi A., primary, Koushyar, Sarah, primary, Furic, Luc, primary, Cullinane, Carleen, primary, Clarkson, Richard W., primary, Smalley, Matthew J., primary, Simpson, Kaylene J., primary, Phesse, Toby J., primary, Shepherd, Peter R., primary, Humbert, Patrick O., primary, Sansom, Owen J., primary, and Phillips, Wayne A., primary

Published
2023
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13. Supp Legends and Table S1 and S2 from Frizzled-7 Is Required for Wnt Signaling in Gastric Tumors with and Without Apc Mutations

Author

Flanagan, Dustin J., primary, Barker, Nick, primary, Costanzo, Natasha S. Di, primary, Mason, Elizabeth A., primary, Gurney, Austin, primary, Meniel, Valerie S., primary, Koushyar, Sarah, primary, Austin, Chloe R., primary, Ernst, Matthias, primary, Pearson, Helen B., primary, Boussioutas, Alex, primary, Clevers, Hans, primary, Phesse, Toby J., primary, and Vincan, Elizabeth, primary

Published
2023
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14. Data from Frizzled-7 Is Required for Wnt Signaling in Gastric Tumors with and Without Apc Mutations

Author

Flanagan, Dustin J., primary, Barker, Nick, primary, Costanzo, Natasha S. Di, primary, Mason, Elizabeth A., primary, Gurney, Austin, primary, Meniel, Valerie S., primary, Koushyar, Sarah, primary, Austin, Chloe R., primary, Ernst, Matthias, primary, Pearson, Helen B., primary, Boussioutas, Alex, primary, Clevers, Hans, primary, Phesse, Toby J., primary, and Vincan, Elizabeth, primary

Published
2023
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15. Fig S7 from Frizzled-7 Is Required for Wnt Signaling in Gastric Tumors with and Without Apc Mutations

Author

Flanagan, Dustin J., primary, Barker, Nick, primary, Costanzo, Natasha S. Di, primary, Mason, Elizabeth A., primary, Gurney, Austin, primary, Meniel, Valerie S., primary, Koushyar, Sarah, primary, Austin, Chloe R., primary, Ernst, Matthias, primary, Pearson, Helen B., primary, Boussioutas, Alex, primary, Clevers, Hans, primary, Phesse, Toby J., primary, and Vincan, Elizabeth, primary

Published
2023
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17. Data from PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

Author

Sakthianandeswaren, Anuratha, primary, Christie, Michael, primary, D'Andreti, Carla, primary, Tsui, Cary, primary, Jorissen, Robert N., primary, Li, Shan, primary, Fleming, Nicholas I., primary, Gibbs, Peter, primary, Lipton, Lara, primary, Malaterre, Jordane, primary, Ramsay, Robert G., primary, Phesse, Toby J., primary, Ernst, Matthias, primary, Jeffery, Rosemary E., primary, Poulsom, Richard, primary, Leedham, Simon J., primary, Segditsas, Stefania, primary, Tomlinson, Ian P. M., primary, Bernhard, Oliver K., primary, Simpson, Richard J., primary, Walker, Francesca, primary, Faux, Maree C., primary, Church, Nicole, primary, Catimel, Bruno, primary, Flanagan, Dustin J., primary, Vincan, Elizabeth, primary, and Sieber, Oliver M., primary

Published
2023
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18. Supplementary Methods and Materials from PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

Author

Sakthianandeswaren, Anuratha, primary, Christie, Michael, primary, D'Andreti, Carla, primary, Tsui, Cary, primary, Jorissen, Robert N., primary, Li, Shan, primary, Fleming, Nicholas I., primary, Gibbs, Peter, primary, Lipton, Lara, primary, Malaterre, Jordane, primary, Ramsay, Robert G., primary, Phesse, Toby J., primary, Ernst, Matthias, primary, Jeffery, Rosemary E., primary, Poulsom, Richard, primary, Leedham, Simon J., primary, Segditsas, Stefania, primary, Tomlinson, Ian P. M., primary, Bernhard, Oliver K., primary, Simpson, Richard J., primary, Walker, Francesca, primary, Faux, Maree C., primary, Church, Nicole, primary, Catimel, Bruno, primary, Flanagan, Dustin J., primary, Vincan, Elizabeth, primary, and Sieber, Oliver M., primary

Published
2023
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19. Supplementary Figures 1-3 from PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

Author

Sakthianandeswaren, Anuratha, primary, Christie, Michael, primary, D'Andreti, Carla, primary, Tsui, Cary, primary, Jorissen, Robert N., primary, Li, Shan, primary, Fleming, Nicholas I., primary, Gibbs, Peter, primary, Lipton, Lara, primary, Malaterre, Jordane, primary, Ramsay, Robert G., primary, Phesse, Toby J., primary, Ernst, Matthias, primary, Jeffery, Rosemary E., primary, Poulsom, Richard, primary, Leedham, Simon J., primary, Segditsas, Stefania, primary, Tomlinson, Ian P. M., primary, Bernhard, Oliver K., primary, Simpson, Richard J., primary, Walker, Francesca, primary, Faux, Maree C., primary, Church, Nicole, primary, Catimel, Bruno, primary, Flanagan, Dustin J., primary, Vincan, Elizabeth, primary, and Sieber, Oliver M., primary

Published
2023
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20. Supplementary Tables 1-2 from PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

Author

Sakthianandeswaren, Anuratha, primary, Christie, Michael, primary, D'Andreti, Carla, primary, Tsui, Cary, primary, Jorissen, Robert N., primary, Li, Shan, primary, Fleming, Nicholas I., primary, Gibbs, Peter, primary, Lipton, Lara, primary, Malaterre, Jordane, primary, Ramsay, Robert G., primary, Phesse, Toby J., primary, Ernst, Matthias, primary, Jeffery, Rosemary E., primary, Poulsom, Richard, primary, Leedham, Simon J., primary, Segditsas, Stefania, primary, Tomlinson, Ian P. M., primary, Bernhard, Oliver K., primary, Simpson, Richard J., primary, Walker, Francesca, primary, Faux, Maree C., primary, Church, Nicole, primary, Catimel, Bruno, primary, Flanagan, Dustin J., primary, Vincan, Elizabeth, primary, and Sieber, Oliver M., primary

Published
2023
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21. RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis

Author

Rickard, James A., O’Donnell, Joanne A., Evans, Joseph M., Lalaoui, Najoua, Poh, Ashleigh R., Rogers, TeWhiti, Vince, James E., Lawlor, Kate E., Ninnis, Robert L., Anderton, Holly, Hall, Cathrine, Spall, Sukhdeep K., Phesse, Toby J., Abud, Helen E., Cengia, Louise H., Corbin, Jason, Mifsud, Sandra, Di Rago, Ladina, Metcalf, Donald, Ernst, Matthias, Dewson, Grant, Roberts, Andrew W., Alexander, Warren S., Murphy, James M., Ekert, Paul G., Masters, Seth L., Vaux, David L., Croker, Ben A., Gerlic, Motti, and Silke, John

Published
2014
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29. Focal Adhesion Kinase Is Required for Intestinal Regeneration and Tumorigenesis Downstream of Wnt/c-Myc Signaling

Author

Ashton, Gabrielle H., Morton, Jennifer P., Myant, Kevin, Phesse, Toby J., Ridgway, Rachel A., Marsh, Victoria, Wilkins, Julie A., Athineos, Dimitris, Muncan, Vanesa, Kemp, Richard, Neufeld, Kristi, Clevers, Hans, Brunton, Valerie, Winton, Douglas J., Wang, Xiaoyan, Sears, Rosalie C., Clarke, Alan R., Frame, Margaret C., and Sansom, Owen J.

Published
2010
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32. Mbd2 enables tumourigenesis within the intestine while preventing tumour‐promoting inflammation

Author

May, Stephanie, Owen, Heather, Phesse, Toby J, Greenow, Kirsty R, Jones, Gareth‐Rhys, Blackwood, Adam, Cook, Peter C, Towers, Christopher, Gallimore, Awen M, Williams, Geraint T, Stürzl, Michael, Britzen‐Laurent, Nathalie, Sansom, Owen J, MacDonald, Andrew S, Bird, Adrian P, Clarke, Alan R, and Parry, Lee

Subjects
Mice, Knockout, Original Paper, DSS colitis, Genes, APC, epigenetics, Dextran Sulfate, DNA Methylation, Th1 Cells, Colitis, Original Papers, Epigenesis, Genetic, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Disease Models, Animal, Cell Transformation, Neoplastic, Th2 Cells, colon cancer, inflammation, Intestinal Neoplasms, Neoplastic Stem Cells, Animals, Intestinal Mucosa, Signal Transduction
Abstract

Epigenetic regulation plays a key role in the link between inflammation and cancer. Here we examine Mbd2, which mediates epigenetic transcriptional silencing by binding to methylated DNA. In separate studies the Mbd2 −/− mouse has been shown (1) to be resistant to intestinal tumourigenesis and (2) to have an enhanced inflammatory/immune response, observations that are inconsistent with the links between inflammation and cancer. To clarify its role in tumourigenesis and inflammation, we used constitutive and conditional models of Mbd2 deletion to explore its epithelial and non‐epithelial roles in the intestine. Using a conditional model, we found that suppression of intestinal tumourigenesis is due primarily to the absence of Mbd2 within the epithelia. Next, we demonstrated, using the DSS colitis model, that non‐epithelial roles of Mbd2 are key in preventing the transition from acute to tumour‐promoting chronic inflammation. Combining models revealed that prior to inflammation the altered Mbd2 −/− immune response plays a role in intestinal tumour suppression. However, following inflammation the intestine converts from tumour suppressive to tumour promoting. To summarise, in the intestine the normal function of Mbd2 is exploited by cancer cells to enable tumourigenesis, while in the immune system it plays a key role in preventing tumour‐enabling inflammation. Which role is dominant depends on the inflammation status of the intestine. As environmental interactions within the intestine can alter DNA methylation patterns, we propose that Mbd2 plays a key role in determining whether these interactions are anti‐ or pro‐tumourigenic and this makes it a useful new epigenetic model for inflammation‐associated carcinogenesis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Published
2018

37. Frizzled-7 is required for Wnt signaling in gastric tumors with and without Apc mutations

Author

Flanagan, Dustin, Barker, Nick, Di Costanzo, Natasha S, Mason, Elizabeth Anne, Gurney, Austin, Meniel, Valerie S, Koushyar, Sarah, Austin, Chloe R, Pearson, Helen B, Boussioutas, Alex, Clevers, Hans, Phesse, Toby J, Vincan, Elisabeth, Flanagan, Dustin, Barker, Nick, Di Costanzo, Natasha S, Mason, Elizabeth Anne, Gurney, Austin, Meniel, Valerie S, Koushyar, Sarah, Austin, Chloe R, Pearson, Helen B, Boussioutas, Alex, Clevers, Hans, Phesse, Toby J, and Vincan, Elisabeth

Abstract

A subset of gastric cancer (GC) patients have mutations in genes that participate in or regulate Wnt signaling at the level of ligand (Wnt) receptor (Fzd) binding. Moreover, increased Fzd expression is associated with poor clinical outcome. Despite these findings, there are no in vivo studies investigating the potential of targeting Wnt receptors for treating GC, and the specific Wnt receptor transmitting oncogenic Wnt signaling in GC is unknown. Here we use inhibitors of Wnt/Fzd (OMP-18R5/Vantictumab) and conditional gene deletion to test the therapeutic potential of targeting Wnt signaling in preclinical models of intestinal-type gastric cancer and ex vivo organoid cultures. Pharmacological targeting of Fzd inhibited the growth of gastric adenomas in vivo. We identified Fzd7 to be the predominant Wnt receptor responsible for transmitting Wnt signaling in human gastric cancer cells and mouse models of GC, whereby Fzd7-deficient cells were retained in gastric adenomas but were unable to respond to Wnt signals and consequently failed to proliferate. Genetic deletion of Fzd7 or treatment with Vantictumab was sufficient to inhibit the growth of gastric adenomas with or without mutations to Apc. Vantictumab is currently in phase Ib clinical trials for advanced pancreatic, lung, and breast cancer. Our data extend the scope of patients that may benefit from this therapeutic approach as we demonstrate that this drug will be effective in treating gastric cancer patients regardless of Apc mutation status.

Published
2019

39. Erratum : Rapid loss of intestinal crypts upon conditional deletion of the Wnt/Tcf-4 Target Gene c-Myc (Molecular and Cellular Biology (2006) 26:22 (8418-8426) DOI: 10.1128/MCB.00821-06)

Author

Muncan, Vanesa, Sansom, Owen J., Tertoolen, Leon, Phesse, Toby J., Begthel, Harry, Sancho, Elena, Cole, Alicia M., Gregorieff, Alex, De Alboran, Ignacio Moreno, Clevers, Hans, and Clarke, Alan R.

Subjects
Cell Biology, Molecular Biology
Abstract

Page 8423, Fig. 5A: The radioactive bands in the upper panel and the RNA bands in the lower panel were inadvertently duplicated. The corrected image, which reflects the original experimental data from 2005, should appear as shown below. This correction does not alter the conclusions of the article. We regret this error and any confusion it may have caused

Published
2018

42. Frizzled-7 Is Required for Wnt Signaling in Gastric Tumors with and Without Apc Mutations

Author

Flanagan, Dustin J., primary, Barker, Nick, additional, Costanzo, Natasha S. Di, additional, Mason, Elizabeth A., additional, Gurney, Austin, additional, Meniel, Valerie S., additional, Koushyar, Sarah, additional, Austin, Chloe R., additional, Ernst, Matthias, additional, Pearson, Helen B., additional, Boussioutas, Alex, additional, Clevers, Hans, additional, Phesse, Toby J., additional, and Vincan, Elizabeth, additional

Published
2019
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43. Correction for Muncan et al., 'Rapid Loss of Intestinal Crypts upon Conditional Deletion of the Wnt/Tcf-4 Target Gene c-'

Author

Muncan, Vanesa, Sansom, Owen J, Tertoolen, Leon, Phesse, Toby J, Begthel, Harry, Sancho, Elena, Cole, Alicia M, Gregorieff, Alex, Moreno de Alboran, Ignacio, Clevers, Hans, Clarke, Alan R, Muncan, Vanesa, Sansom, Owen J, Tertoolen, Leon, Phesse, Toby J, Begthel, Harry, Sancho, Elena, Cole, Alicia M, Gregorieff, Alex, Moreno de Alboran, Ignacio, Clevers, Hans, and Clarke, Alan R

Published
2018

44. Correction for Muncan et al., 'Rapid Loss of Intestinal Crypts upon Conditional Deletion of the Wnt/Tcf-4 Target Gene c- Myc'.

Author

Child Health, Regenerative Medicine and Stem Cells, Cancer, Hubrecht Institute with UMC, Muncan, Vanesa, Sansom, Owen J., Tertoolen, Leon, Phesse, Toby J., Begthel, Harry, Sancho, Elena, Cole, Alicia M., Gregorieff, Alex, De Alboran, Ignacio Moreno, Clevers, Hans, Clarke, Alan R., Child Health, Regenerative Medicine and Stem Cells, Cancer, Hubrecht Institute with UMC, Muncan, Vanesa, Sansom, Owen J., Tertoolen, Leon, Phesse, Toby J., Begthel, Harry, Sancho, Elena, Cole, Alicia M., Gregorieff, Alex, De Alboran, Ignacio Moreno, Clevers, Hans, and Clarke, Alan R.

Published
2018

45. Identification of Pik3ca Mutation as a Genetic Driver of Prostate Cancer That Cooperates with Pten Loss to Accelerate Progression and Castration-Resistant Growth

Author

Pearson, Helen B., primary, Li, Jason, additional, Meniel, Valerie S., additional, Fennell, Christina M., additional, Waring, Paul, additional, Montgomery, Karen G., additional, Rebello, Richard J., additional, Macpherson, Arthi A., additional, Koushyar, Sarah, additional, Furic, Luc, additional, Cullinane, Carleen, additional, Clarkson, Richard W., additional, Smalley, Matthew J., additional, Simpson, Kaylene J., additional, Phesse, Toby J., additional, Shepherd, Peter R., additional, Humbert, Patrick O., additional, Sansom, Owen J., additional, and Phillips, Wayne A., additional

Published
2018
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46. Loss of the Wnt receptor frizzled 7 in the mouse gastric epithelium is deleterious and triggers rapid repopulation in vivo

Author

Flanagan, Dustin J, Barker, Nick, Nowell, Cameron J, Clevers, Hans, Ernst, Matthias, Phesse, Toby J, Vincan, Elizabeth, Flanagan, Dustin J, Barker, Nick, Nowell, Cameron J, Clevers, Hans, Ernst, Matthias, Phesse, Toby J, and Vincan, Elizabeth

Abstract

The gastric epithelium consists of tubular glandular units, each containing several differentiated cell types, and populations of stem cells, which enable the stomach to secrete the acid, mucus and various digestive enzymes required for its function. Very little is known about which cell signalling pathways are required for homeostasis of the gastric epithelium. Many diseases, such as cancer, arise as a result of deregulation of signalling pathways that regulate homeostasis of the diseased organ. Therefore, it is important to understand the biology of how normal conditions are maintained in a tissue to help inform the mechanisms driving disease in that same tissue, and to identify potential points of therapeutic intervention. Wnt signalling regulates several cell functions, including proliferation, differentiation and migration, and plays a crucial role during homeostasis of several tissues, including the intestinal epithelium. Wnt3a is required in the culture medium of gastric organoids, suggesting it is also important for the homeostasis of the gastric epithelium, but this has not been investigated in vivo Here, we show that the Wnt receptor frizzled 7 (Fzd7), which is required for the homeostasis of the intestine, is expressed in the gastric epithelium and is required for gastric organoid growth. Gastric-specific loss of Fzd7 in the adult gastric epithelium of mice is deleterious and triggers rapid epithelial repopulation, which we believe is the first observation of this novel function for this tissue. Taken together, these data provide functional evidence of a crucial role for Wnt signalling, via the Fzd7 receptor, during homeostasis of the gastric epithelium.

Published
2017

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