32 results on '"Mrowinska A"'
Search Results
2. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer
- Author
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Najumudeen, Arafath K., Ceteci, Fatih, Fey, Sigrid K., Hamm, Gregory, Steven, Rory T., Hall, Holly, Nikula, Chelsea J., Dexter, Alex, Murta, Teresa, Race, Alan M., Sumpton, David, Vlahov, Nikola, Gay, David M., Knight, John R. P., Jackstadt, Rene, Leach, Joshua D. G., Ridgway, Rachel A., Johnson, Emma R., Nixon, Colin, Hedley, Ann, Gilroy, Kathryn, Clark, William, Malla, Sudhir B., Dunne, Philip D., Rodriguez-Blanco, Giovanny, Critchlow, Susan E., Mrowinska, Agata, Malviya, Gaurav, Solovyev, Dmitry, Brown, Gavin, Lewis, David Y., Mackay, Gillian M., Strathdee, Douglas, Tardito, Saverio, Gottlieb, Eyal, Takats, Zoltan, Barry, Simon T., Goodwin, Richard J. A., Bunch, Josephine, Bushell, Martin, Campbell, Andrew D., and Sansom, Owen J.
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- 2021
- Full Text
- View/download PDF
3. Mannose impairs tumour growth and enhances chemotherapy
- Author
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Gonzalez, Pablo Sierra, O’Prey, James, Cardaci, Simone, Barthet, Valentin J. A., Sakamaki, Jun-ichi, Beaumatin, Florian, Roseweir, Antonia, Gay, David M., Mackay, Gillian, Malviya, Gaurav, Kania, Elżbieta, Ritchie, Shona, Baudot, Alice D., Zunino, Barbara, Mrowinska, Agata, Nixon, Colin, Ennis, Darren, Hoyle, Aoisha, Millan, David, McNeish, Iain A., Sansom, Owen J., Edwards, Joanne, and Ryan, Kevin M.
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- 2018
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- View/download PDF
4. 18F-Fluciclovine PET metabolic imaging reveals prostate cancer tumour heterogeneity associated with disease resistance to androgen deprivation therapy
- Author
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Malviya, Gaurav, Patel, Rachana, Salji, Mark, Martinez, Rafael S., Repiscak, Peter, Mui, Ernest, Champion, Susan, Mrowinska, Agata, Johnson, Emma, AlRasheedi, Maha, Pimlott, Sally, Lewis, David, and Leung, Hing Y.
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- 2020
- Full Text
- View/download PDF
5. A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts
- Author
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Max Nobis, David Herrmann, Sean C. Warren, Shereen Kadir, Wilfred Leung, Monica Killen, Astrid Magenau, David Stevenson, Morghan C. Lucas, Nadine Reischmann, Claire Vennin, James R.W. Conway, Alice Boulghourjian, Anaiis Zaratzian, Andrew M. Law, David Gallego-Ortega, Christopher J. Ormandy, Stacey N. Walters, Shane T. Grey, Jacqueline Bailey, Tatyana Chtanova, Julian M.W. Quinn, Paul A. Baldock, Peter I. Croucher, Juliane P. Schwarz, Agata Mrowinska, Lei Zhang, Herbert Herzog, Andrius Masedunskas, Edna C. Hardeman, Peter W. Gunning, Gonzalo del Monte-Nieto, Richard P. Harvey, Michael S. Samuel, Marina Pajic, Ewan J. McGhee, Anna-Karin E. Johnsson, Owen J. Sansom, Heidi C.E. Welch, Jennifer P. Morton, Douglas Strathdee, Kurt I. Anderson, and Paul Timpson
- Subjects
intravital imaging ,pancreatic cancer ,breast cancer ,actin ,small GTPase RhoA ,FLIM-FRET ,biosensors ,immunology ,development ,cell biology ,Biology (General) ,QH301-705.5 - Abstract
The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time.
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- 2017
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6. Data from Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer
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Patel, Rachana, primary, Brzezinska, Elspeth A., primary, Repiscak, Peter, primary, Ahmad, Imran, primary, Mui, Ernest, primary, Gao, Meiling, primary, Blomme, Arnaud, primary, Harle, Victoria, primary, Tan, Ee Hong, primary, Malviya, Gaurav, primary, Mrowinska, Agata, primary, Loveridge, Carolyn J., primary, Rushworth, Linda K., primary, Edwards, Joanne, primary, Ntala, Chara, primary, Nixon, Colin, primary, Hedley, Ann, primary, Mackay, Gillian, primary, Tardito, Saverio, primary, Sansom, Owen J., primary, and Leung, Hing Y., primary
- Published
- 2023
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- View/download PDF
7. Supplementary Data from Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer
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Patel, Rachana, primary, Brzezinska, Elspeth A., primary, Repiscak, Peter, primary, Ahmad, Imran, primary, Mui, Ernest, primary, Gao, Meiling, primary, Blomme, Arnaud, primary, Harle, Victoria, primary, Tan, Ee Hong, primary, Malviya, Gaurav, primary, Mrowinska, Agata, primary, Loveridge, Carolyn J., primary, Rushworth, Linda K., primary, Edwards, Joanne, primary, Ntala, Chara, primary, Nixon, Colin, primary, Hedley, Ann, primary, Mackay, Gillian, primary, Tardito, Saverio, primary, Sansom, Owen J., primary, and Leung, Hing Y., primary
- Published
- 2023
- Full Text
- View/download PDF
8. Data from Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer
- Author
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Hing Y. Leung, Owen J. Sansom, Saverio Tardito, Gillian Mackay, Ann Hedley, Colin Nixon, Chara Ntala, Joanne Edwards, Linda K. Rushworth, Carolyn J. Loveridge, Agata Mrowinska, Gaurav Malviya, Ee Hong Tan, Victoria Harle, Arnaud Blomme, Meiling Gao, Ernest Mui, Imran Ahmad, Peter Repiscak, Elspeth A. Brzezinska, and Rachana Patel
- Abstract
Inhibition of the androgen receptor (AR) is the main strategy to treat advanced prostate cancers. AR-independent treatment-resistant prostate cancer is a major unresolved clinical problem. Patients with prostate cancer with alterations in canonical WNT pathway genes, which lead to β-catenin activation, are refractory to AR-targeted therapies. Here, using clinically relevant murine prostate cancer models, we investigated the significance of β-catenin activation in prostate cancer progression and treatment resistance. β-Catenin activation, independent of the cell of origin, cooperated with Pten loss to drive AR-independent castration-resistant prostate cancer. Prostate tumors with β-catenin activation relied on the noncanonical WNT ligand WNT5a for sustained growth. WNT5a repressed AR expression and maintained the expression of c-Myc, an oncogenic effector of β-catenin activation, by mediating nuclear localization of NFκBp65 and β-catenin. Overall, WNT/β-catenin and AR signaling are reciprocally inhibited. Therefore, inhibiting WNT/β-catenin signaling by limiting WNT secretion in concert with AR inhibition may be useful for treating prostate cancers with alterations in WNT pathway genes.Significance:Targeting of both AR and WNT/β-catenin signaling may be required to treat prostate cancers that exhibit alterations of the WNT pathway.
- Published
- 2023
9. Supplementary Data from Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer
- Author
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Hing Y. Leung, Owen J. Sansom, Saverio Tardito, Gillian Mackay, Ann Hedley, Colin Nixon, Chara Ntala, Joanne Edwards, Linda K. Rushworth, Carolyn J. Loveridge, Agata Mrowinska, Gaurav Malviya, Ee Hong Tan, Victoria Harle, Arnaud Blomme, Meiling Gao, Ernest Mui, Imran Ahmad, Peter Repiscak, Elspeth A. Brzezinska, and Rachana Patel
- Abstract
The supplementary file contains details of the materials and methods used in the manuscript. File also contains supplementary figures S1 to S3 describing in details the murine model used to study role of activated ß-catenin in prostate cancer progression. Supplementary figure S4 describes the murine orthograft model generated to study mechanistic details. Supplementary figure S5 describes the metabolic profile of primary murine prostate cancer cells with Pten loss and ß-catenin activation and figures S6 and S7 show the effects of combining ADT with inhibition of WNT signalling.
- Published
- 2023
10. Intravital FRAP Imaging using an E-cadherin-GFP Mouse Reveals Disease- and Drug-Dependent Dynamic Regulation of Cell-Cell Junctions in Live Tissue
- Author
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Zahra Erami, David Herrmann, Sean C. Warren, Max Nobis, Ewan J. McGhee, Morghan C. Lucas, Wilfred Leung, Nadine Reischmann, Agata Mrowinska, Juliane P. Schwarz, Shereen Kadir, James R.W. Conway, Claire Vennin, Saadia A. Karim, Andrew D. Campbell, David Gallego-Ortega, Astrid Magenau, Kendelle J. Murphy, Rachel A. Ridgway, Andrew M. Law, Stacey N. Walters, Shane T. Grey, David R. Croucher, Lei Zhang, Herbert Herzog, Edna C. Hardeman, Peter W. Gunning, Christopher J. Ormandy, T.R. Jeffry Evans, Douglas Strathdee, Owen J. Sansom, Jennifer P. Morton, Kurt I. Anderson, and Paul Timpson
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intravital imaging ,FRAP ,E-cadherin ,Src-kinase ,pancreatic cancer ,invasion and metastasis ,cell adhesion and migration ,Kras ,p53 ,Biology (General) ,QH301-705.5 - Abstract
E-cadherin-mediated cell-cell junctions play a prominent role in maintaining the epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here we generated an E-cadherin-GFP mouse that enables intravital photobleaching and quantification of E-cadherin mobility in live tissue without affecting normal biology. We demonstrate the broad applications of this mouse by examining E-cadherin regulation in multiple tissues, including mammary, brain, liver, and kidney tissue, while specifically monitoring E-cadherin mobility during disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression. FRAP in the E-cadherin-GFP mouse, therefore, promises to be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments.
- Published
- 2016
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11. Human-correlated genetic HCC models identify combination therapy for precision medicine
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Miryam Müller, Stephanie May, Holly Hall, Timothy J. Kendall, Lynn McGarry, Lauriane Blukacz, Sandro Nuciforo, Thomas Jamieson, Narisa Phinichkusolchit, Sandeep Dhayade, Jack Leslie, Joep Sprangers, Gaurav Malviya, Agata Mrowinska, Emma Johnson, Misti McCain, John Halpin, Christos Kiourtis, Anastasia Georgakopoulou, Colin Nixon, William Clark, Robin Shaw, Ann Hedley, Thomas M. Drake, Ee Hong Tan, Matt Neilson, Daniel J. Murphy, David Lewis, Helen L. Reeves, Derek A. Mann, Karen Blyth, Markus H. Heim, Leo M. Carlin, Owen J. Sansom, Crispin Miller, and Thomas G. Bird
- Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer related mortality worldwide. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulated progressive driver mutations, with hepatocytes the most likely cell of origin. However, the landscape of driver mutations in HCC is independent of the underlying aetiologies. Despite an increasing range of systemic treatment options for advanced HCC outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC. We generated over twenty-five new genetically-driven in vivo and in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance, and metastasis to distant organs. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human-mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with histopathology. In a proof-of-principle analysis, we verified response to standard of care treatment and used a linked in vitro-in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not been linked to HCC treatment before. Cladribine acts in a highly effective subtype-specific manner in combination with standard of care therapy.
- Published
- 2022
12. Human-correlated genetic HCC models identify combination therapy for precision medicine
- Author
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Müller, Miryam, primary, May, Stephanie, additional, Hall, Holly, additional, Kendall, Timothy J., additional, McGarry, Lynn, additional, Blukacz, Lauriane, additional, Nuciforo, Sandro, additional, Jamieson, Thomas, additional, Phinichkusolchit, Narisa, additional, Dhayade, Sandeep, additional, Leslie, Jack, additional, Sprangers, Joep, additional, Malviya, Gaurav, additional, Mrowinska, Agata, additional, Johnson, Emma, additional, McCain, Misti, additional, Halpin, John, additional, Kiourtis, Christos, additional, Georgakopoulou, Anastasia, additional, Nixon, Colin, additional, Clark, William, additional, Shaw, Robin, additional, Hedley, Ann, additional, Drake, Thomas M., additional, Tan, Ee Hong, additional, Neilson, Matt, additional, Murphy, Daniel J., additional, Lewis, David, additional, Reeves, Helen L., additional, Mann, Derek A., additional, Blyth, Karen, additional, Heim, Markus H., additional, Carlin, Leo M., additional, Sansom, Owen J., additional, Miller, Crispin, additional, and Bird, Thomas G., additional
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- 2022
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- View/download PDF
13. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer
- Author
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Owen J. Sansom, John R. P. Knight, Simon T. Barry, Rachel A. Ridgway, David Sumpton, Rory T. Steven, Giovanny Rodriguez-Blanco, Eyal Gottlieb, Gaurav Malviya, William C. Clark, Douglas Strathdee, Emma R. Johnson, Holly Hall, Alex Dexter, Teresa Murta, David Y. Lewis, Saverio Tardito, Gregory Hamm, Gavin Brown, Colin Nixon, Kathryn Gilroy, Zoltan Takats, Sudhir B Malla, Dmitry Solovyev, Sigrid K. Fey, Fatih Ceteci, Gillian M. Mackay, Susan E. Critchlow, Ann Hedley, Nikola Vlahov, Alan M. Race, Martin Bushell, Andrew D. Campbell, Arafath Kaja Najumudeen, Richard J. A. Goodwin, Josephine Bunch, Chelsea J. Nikula, Agata Mrowinska, Philip D Dunne, Rene Jackstadt, and Joshua D.G. Leach
- Subjects
0303 health sciences ,Mutation ,Mutant ,mTORC1 ,Biology ,medicine.disease_cause ,digestive system diseases ,Glutamine ,03 medical and health sciences ,0302 clinical medicine ,Cancer cell ,Genetics ,medicine ,Cancer research ,Amino acid transporter ,KRAS ,Signal transduction ,neoplasms ,030217 neurology & neurosurgery ,030304 developmental biology - 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
- 2021
14. P53 status determines the role of atophagy in pancreatic tumour development
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Rosenfeldt, Mathias T., O'Prey, Jim, Morton, Jennifer P., Nixon, Colin, MacKay, Gillian, Mrowinska, Agata, Au, Amy, Rai, Taranjit Singh, Zheng, Liang, Ridgway, Rachel, Adams, Peter D., Anderson, Kurt I., Gottlieb, Eyal, Sansom, Owen J., and Ryan, Kevin M.
- Subjects
Pancreatic tumors -- Physiological aspects ,Autophagy (Cytology) -- Health aspects -- Physiological aspects ,Molecular biology -- Research ,Tumor antigens -- Health aspects -- Physiological aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation (1). Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease (2-4). The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles (3,5-12). Here we show, in a humanized geneticallymodified mouse model of pancreatic ductal adenocarcinoma (PDAC), that autophagy's role in tumour development is intrinsically connected to the status of the tumour suppressor p53. Mice with pancreases containing an activated oncogenic allele of Kras (also called Ki-Ras)--the most common mutational event in PDAC (13) --develop a small number of pre-cancerous lesions that stochastically develop into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 or Atg7 accumulate low-grade, pre-malignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC is blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocks tumour progression, but actually accelerates tumour onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumour growth. These findings provide considerable insight into the role of autophagy in cancer and have important implications for autophagy inhibition in cancer therapy. In this regard, we also show that treatment of mice with the autophagy inhibitor hydroxychloroquine, which is currently being used in several clinical trials (14), significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53., To analyse the role of autophagy in pancreatic tumour development we generated mice that contained Cre recombinase driven by the Pdx promoter (which recombines in exocrine and endocrine pancreatic tissue [...]
- Published
- 2013
15. 18F-Fluciclovine PET metabolic imaging reveals prostate cancer tumour heterogeneity associated with disease resistance to androgen deprivation therapy
- Author
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Gaurav Malviya, Maha AlRasheedi, Emma R. Johnson, Rafael S. Martinez, Ernest Mui, Agata Mrowinska, Hing Y. Leung, David Y. Lewis, Peter Repiscak, Mark Salji, Sue Champion, Rachana Patel, and Sally L. Pimlott
- Subjects
Tumour heterogeneity ,business.industry ,Amino acid transporter ,Metabolic imaging ,Cancer ,medicine.disease ,030218 nuclear medicine & medical imaging ,Androgen deprivation therapy ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,medicine.anatomical_structure ,Castration Resistance ,Prostate ,030220 oncology & carcinogenesis ,18F-Fluciclovine (FACBC) ,Cancer cell ,Cancer research ,Medicine ,Immunohistochemistry ,Radiology, Nuclear Medicine and imaging ,business ,Original Research ,Castration-resistant prostate cancer - Abstract
Background Prostate cancer is highly prevalent worldwide. Androgen deprivation therapy (ADT) remains the treatment of choice for incurable prostate cancer, but majority of patients develop disease recurrence following ADT. There is therefore an urgent need for early detection of treatment resistance. Methods Isogenic androgen-responsive (CWR22Res) and castration-resistant (22Rv1) human prostate cancer cells were implanted into the anterior lobes of the prostate in CD-1 Nu mice to generate prostate orthografts. Castrated mice bearing CWR22Res and 22Rv1 orthografts mimic clinical prostate cancer following acute and chronic ADT, respectively. 18F-Fluciclovine (1-amino-3-fluorocyclobutane-1-carboxylic acid) with a radiochemical purity of > 99% was produced on a FASTlab synthesiser. Ki67 staining in endpoint orthografts was studied. Western blot, quantitative RT-PCR and next-generation sequencing transcriptomic analyses were performed to assess the expression levels of amino acid transporters (including LAT1 and ASCT2, which have been implicated for Fluciclovine uptake). Longitudinal metabolic imaging with 18F-Fluciclovine-based positron emission tomography (PET) was performed to study tumour response following acute and chronic ADT. Results Both immunohistochemistry analysis of endpoint prostate tumours and longitudinal 18F-Fluciclovine imaging revealed tumour heterogeneity, particularly following ADT, with in vivo 18F-Fluciclovine uptake correlating to viable cancer cells in both androgen-proficient and castrated environment. Highlighting tumour subpopulation following ADT, both SUVpeak and coefficient of variation (CoV) values of 18F-Fluciclovine uptake are consistent with tumour heterogeneity revealed by immunohistochemistry. We studied the expression of amino acid transporters (AATs) for 18F-Fluciclovine, namely LAT1 (SLC7A5 and SLC3A2) and ASCT2 (SLC1A5). SLC7A5 and SLC3A2 were expressed at relatively high levels in 22Rv1 castration-resistant orthografts following chronic ADT (modelling clinical castration-resistant disease), while SLC1A5 was preferentially expression in CWR22Res tumours following acute ADT. Additional AATs such as SLC43A2 (LAT4) were shown to be upregulated following chronic ADT by transcriptomic analysis; their role in Fluciclovine uptake warrants investigation. Conclusion We studied in vivo 18F-Fluciclovine uptake in human prostate cancer orthograft models following acute and chronic ADT. 18F-Fluciclovine uptakes highlight tumour heterogeneity that may explain castration resistance and can be exploited as a clinical biomarker.
- Published
- 2020
16. Targeting mTOR dependency in pancreatic cancer
- Author
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Morran, Douglas C, Wu, Jianmin, Jamieson, Nigel B, Mrowinska, Agata, Kalna, Gabriela, Karim, Saadia A, Au, Amy Y M, Scarlett, Christopher J, Chang, David K, Pajak, Malgorzata Z, Oien, Karin A, McKay, Colin J, Carter, C Ross, Gillen, Gerry, Champion, Sue, Pimlott, Sally L, Anderson, Kurt I, Evans, T R Jeffry, Grimmond, Sean M, Biankin, Andrew V, Sansom, Owen J, and Morton, Jennifer P
- Published
- 2014
- Full Text
- View/download PDF
17. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer
- Author
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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
18. Additional file 1 of 18F-Fluciclovine PET metabolic imaging reveals prostate cancer tumour heterogeneity associated with disease resistance to androgen deprivation therapy
- Author
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Gaurav Malviya, Rachana Patel, Salji, Mark, Martinez, Rafael S., Repiscak, Peter, Mui, Ernest, Champion, Susan, Mrowinska, Agata, Johnson, Emma, AlRasheedi, Maha, Pimlott, Sally, Lewis, David, and Leung, Hing Y.
- Subjects
InformationSystems_INFORMATIONSTORAGEANDRETRIEVAL ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,ComputingMilieux_COMPUTERSANDEDUCATION ,Data_FILES ,ComputerApplications_COMPUTERSINOTHERSYSTEMS - Abstract
Additional file 1. Supplementary information.
- Published
- 2020
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19. Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer
- Author
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Patel, Rachana, primary, Brzezinska, Elspeth A., additional, Repiscak, Peter, additional, Ahmad, Imran, additional, Mui, Ernest, additional, Gao, Meiling, additional, Blomme, Arnaud, additional, Harle, Victoria, additional, Tan, Ee Hong, additional, Malviya, Gaurav, additional, Mrowinska, Agata, additional, Loveridge, Carolyn J., additional, Rushworth, Linda K., additional, Edwards, Joanne, additional, Ntala, Chara, additional, Nixon, Colin, additional, Hedley, Ann, additional, Mackay, Gillian, additional, Tardito, Saverio, additional, Sansom, Owen J., additional, and Leung, Hing Y., additional
- Published
- 2020
- Full Text
- View/download PDF
20. A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts
- Author
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Max Nobis, Tatyana Chtanova, Marina Pajic, Douglas Strathdee, Peter W. Gunning, Stacey N. Walters, Peter I. Croucher, Juliane P. Schwarz, Edna C. Hardeman, Julian M. W. Quinn, Kurt I. Anderson, Alice Boulghourjian, Agata Mrowinska, James R.W. Conway, Owen J. Sansom, Christopher J. Ormandy, Nadine Reischmann, David Herrmann, Paul Timpson, Monica J. Killen, Heidi C.E. Welch, Lei Zhang, Jennifer P. Morton, Michael S. Samuel, Andrius Masedunskas, Claire Vennin, Paul A. Baldock, Shereen Kadir, Jacqueline Bailey, Anna-Karin E. Johnsson, Richard P. Harvey, Andrew M. K. Law, Wilfred Leung, Ewan J. McGhee, Morghan C. Lucas, Gonzalo del Monte-Nieto, Anaiis Zaratzian, Herbert Herzog, Astrid Magenau, David A. Stevenson, Shane T. Grey, Sean C. Warren, David Gallego-Ortega, Killen, Monica [0000-0001-9832-0421], Welch, Heidi Christine Erika [0000-0001-7865-7000], Apollo - University of Cambridge Repository, Nobis, Max, Herrmann, David, Warren, Sean C, Kadir, Shereen, Samuel, Michael S, and Timpson, Paul
- Subjects
0301 basic medicine ,rho GTP-Binding Proteins ,RHOA ,Intravital Microscopy ,Neutrophils ,pancreatic cancer ,Dasatinib ,Biosensing Techniques ,Mechanotransduction, Cellular ,immunology ,Mice ,Cell Movement ,cell biology ,Intestine, Small ,Fluorescence Resonance Energy Transfer ,Small GTPase ,lcsh:QH301-705.5 ,Regulation of gene expression ,small GTPase RhoA ,0601 Biochemistry and Cell Biology, 1116 Medical Physiology ,Cell biology ,Female ,actin biosensors ,actin ,Intravital microscopy ,FLIM-FRET ,Motility ,Antineoplastic Agents ,Mice, Transgenic ,Biology ,Osteocytes ,Time-Lapse Imaging ,General Biochemistry, Genetics and Molecular Biology ,Bone and Bones ,03 medical and health sciences ,Erlotinib Hydrochloride ,breast cancer ,Mammary Glands, Animal ,In vivo ,Animals ,development ,Actin ,Mammary Neoplasms, Experimental ,biosensors ,Pancreatic Neoplasms ,030104 developmental biology ,Förster resonance energy transfer ,lcsh:Biology (General) ,Gene Expression Regulation ,biology.protein ,intravital imaging ,rhoA GTP-Binding Protein - Abstract
The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time. Nobis et al. generated a RhoA-FRET biosensor mouse to characterize and quantify the spatiotemporal distribution of RhoA activity in native mammalian tissues in vivo during development and disease progression. They show that RhoA activity is tightly regulated during various normal biological processes and is co-opted in disease settings, such as invasive breast and pancreatic cancers. Refereed/Peer-reviewed
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- 2019
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21. Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer
- Author
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Imran Ahmad, Rachana Patel, Agata Mrowinska, Elspeth A. Brzezinska, Chara Ntala, Victoria Harle, Saverio Tardito, Hing Y. Leung, Linda K. Rushworth, Ee Hong Tan, Gaurav Malviya, Joanne Edwards, Carolyn J. Loveridge, Ann Hedley, Meiling Gao, Gillian M. Mackay, Colin Nixon, Owen J. Sansom, Peter Repiscak, Ernest Mui, and Arnaud Blomme
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Apoptosis ,Wnt-5a Protein ,03 medical and health sciences ,Prostate cancer ,Mice ,0302 clinical medicine ,Prostate ,medicine ,Androgen Receptor Antagonists ,Biomarkers, Tumor ,Tumor Cells, Cultured ,PTEN ,Animals ,Humans ,beta Catenin ,Cell Proliferation ,biology ,business.industry ,Cell growth ,Wnt signaling pathway ,PTEN Phosphohydrolase ,medicine.disease ,Prognosis ,Xenograft Model Antitumor Assays ,Androgen receptor ,WNT5A ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Catenin ,biology.protein ,Cancer research ,business - Abstract
Inhibition of the androgen receptor (AR) is the main strategy to treat advanced prostate cancers. AR-independent treatment-resistant prostate cancer is a major unresolved clinical problem. Patients with prostate cancer with alterations in canonical WNT pathway genes, which lead to β-catenin activation, are refractory to AR-targeted therapies. Here, using clinically relevant murine prostate cancer models, we investigated the significance of β-catenin activation in prostate cancer progression and treatment resistance. β-Catenin activation, independent of the cell of origin, cooperated with Pten loss to drive AR-independent castration-resistant prostate cancer. Prostate tumors with β-catenin activation relied on the noncanonical WNT ligand WNT5a for sustained growth. WNT5a repressed AR expression and maintained the expression of c-Myc, an oncogenic effector of β-catenin activation, by mediating nuclear localization of NFκBp65 and β-catenin. Overall, WNT/β-catenin and AR signaling are reciprocally inhibited. Therefore, inhibiting WNT/β-catenin signaling by limiting WNT secretion in concert with AR inhibition may be useful for treating prostate cancers with alterations in WNT pathway genes. Significance: Targeting of both AR and WNT/β-catenin signaling may be required to treat prostate cancers that exhibit alterations of the WNT pathway.
- Published
- 2019
22. Mannose impairs tumour growth and enhances chemotherapy
- Author
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Owen J. Sansom, Darren Ennis, Joanne Edwards, James O'Prey, Antonia K. Roseweir, Aoisha Hoyle, S. Cardaci, Kevin M. Ryan, Gaurav Malviya, Alice D. Baudot, Colin Nixon, Agata Mrowinska, Barbara Zunino, Jun-ichi Sakamaki, Shona Ritchie, Gillian M. Mackay, Iain A. McNeish, Elżbieta Kania, David Millan, Florian Beaumatin, Valentin J.A. Barthet, Pablo Sierra Gonzalez, and Cancer Research UK
- Subjects
0301 basic medicine ,CELL-SURVIVAL ,Cell ,Mannose ,Administration, Oral ,Apoptosis ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Neoplasms ,Multidisciplinary ,Mannosephosphates ,Drug Synergism ,CANCER ,Multidisciplinary Sciences ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Science & Technology - Other Topics ,AUTOPHAGY ,Female ,RNA Interference ,Glycolysis ,Programmed cell death ,General Science & Technology ,bcl-X Protein ,Down-Regulation ,Mice, Nude ,Antineoplastic Agents ,Pentose phosphate pathway ,METABOLISM ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Cell Proliferation ,HALLMARKS ,Science & Technology ,Mannose-6-Phosphate Isomerase ,Cell growth ,Body Weight ,Mice, Inbred C57BL ,030104 developmental biology ,Glucose ,chemistry ,Cell culture ,Cancer research ,Myeloid Cell Leukemia Sequence 1 Protein ,RESISTANCE - Abstract
It is now well established that tumours undergo changes in cellular metabolism1. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake2, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types.
- Published
- 2017
23. Targeting mTOR dependency in pancreatic cancer
- Author
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Owen J. Sansom, C. Ross Carter, Douglas C. Morran, Karin A. Oien, Amy Au, Saadia A. Karim, Nigel B. Jamieson, Gabriela Kalna, Christopher J. Scarlett, Sue Champion, Kurt I. Anderson, Jianmin Wu, Andrew V. Biankin, T.R. Jeffry Evans, David K. Chang, Malgorzata Z. Pajak, Jennifer P. Morton, Agata Mrowinska, Colin J. McKay, Gerry Gillen, Sally L. Pimlott, and Sean M. Grimmond
- Subjects
Antineoplastic Agents ,medicine.disease_cause ,Drug Administration Schedule ,Metastasis ,Proto-Oncogene Proteins p21(ras) ,Mice ,Cell Line, Tumor ,Pancreatic cancer ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,PTEN ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Sirolimus ,biology ,TOR Serine-Threonine Kinases ,PTEN Phosphohydrolase ,Gastroenterology ,Cancer ,medicine.disease ,Mice, Mutant Strains ,digestive system diseases ,Gemcitabine ,3. Good health ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,Treatment Outcome ,Positron-Emission Tomography ,Mutation ,biology.protein ,Cancer research ,KRAS ,Tumor Suppressor Protein p53 ,Injections, Intraperitoneal ,Carcinoma, Pancreatic Ductal ,medicine.drug - Abstract
Objective: Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease.\ud \ud Design: Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of KrasG12D-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition.\ud \ud Results: We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours.\ud \ud Conclusions: KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future.
- Published
- 2014
24. p53 status determines the role of autophagy in pancreatic tumour development
- Author
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Peter D. Adams, Kurt I. Anderson, Liang Zheng, Kevin M. Ryan, Amy Au, Agata Mrowinska, Mathias T. Rosenfeldt, Gillian M. Mackay, Colin Nixon, Taranjit Singh Rai, Jim O'Prey, Jennifer P. Morton, Owen J. Sansom, Eyal Gottlieb, and Rachel A. Ridgway
- Subjects
Mice, 129 Strain ,ATG5 ,Pancreatic Intraepithelial Neoplasia ,Cellular homeostasis ,Oncogene Protein p21(ras) ,Biology ,medicine.disease_cause ,Autophagy-Related Protein 7 ,Autophagy-Related Protein 5 ,law.invention ,Pentose Phosphate Pathway ,Mice ,law ,Cell Line, Tumor ,Autophagy ,medicine ,Animals ,Humans ,Metabolomics ,Alleles ,Multidisciplinary ,Cancer ,Genes, p53 ,medicine.disease ,Survival Analysis ,Cell biology ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,Disease Models, Animal ,Glucose ,Suppressor ,KRAS ,Tumor Suppressor Protein p53 ,Glycolysis ,Microtubule-Associated Proteins ,Precancerous Conditions ,Carcinoma, Pancreatic Ductal ,Hydroxychloroquine - Abstract
Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation. Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease. The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles. Here we show, in a humanized genetically-modified mouse model of pancreatic ductal adenocarcinoma (PDAC), that autophagy's role in tumour development is intrinsically connected to the status of the tumour suppressor p53. Mice with pancreases containing an activated oncogenic allele of Kras (also called Ki-Ras)--the most common mutational event in PDAC--develop a small number of pre-cancerous lesions that stochastically develop into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 or Atg7 accumulate low-grade, pre-malignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC is blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocks tumour progression, but actually accelerates tumour onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumour growth. These findings provide considerable insight into the role of autophagy in cancer and have important implications for autophagy inhibition in cancer therapy. In this regard, we also show that treatment of mice with the autophagy inhibitor hydroxychloroquine, which is currently being used in several clinical trials, significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53.
- Published
- 2013
25. A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts
- Author
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Nobis, M, Herrmann, D, Warren, SC, Kadir, S, Leung, W, Killen, M, Magenau, A, Stevenson, D, Lucas, MC, Reischmann, N, Vennin, C, Conway, JRW, Boulghourjian, A, Zaratzian, A, Law, AM, Gallego-Ortega, D, Ormandy, CJ, Walters, SN, Grey, ST, Bailey, J, Chtanova, T, Quinn, JMW, Baldock, PA, Croucher, PI, Schwarz, JP, Mrowinska, A, Zhang, L, Herzog, H, Masedunskas, A, Hardeman, EC, Gunning, PW, del Monte-Nieto, G, Harvey, RP, Samuel, MS, Pajic, M, McGhee, EJ, Johnsson, AKE, Sansom, OJ, Welch, HCE, Morton, JP, Strathdee, D, Anderson, KI, Timpson, P, Nobis, M, Herrmann, D, Warren, SC, Kadir, S, Leung, W, Killen, M, Magenau, A, Stevenson, D, Lucas, MC, Reischmann, N, Vennin, C, Conway, JRW, Boulghourjian, A, Zaratzian, A, Law, AM, Gallego-Ortega, D, Ormandy, CJ, Walters, SN, Grey, ST, Bailey, J, Chtanova, T, Quinn, JMW, Baldock, PA, Croucher, PI, Schwarz, JP, Mrowinska, A, Zhang, L, Herzog, H, Masedunskas, A, Hardeman, EC, Gunning, PW, del Monte-Nieto, G, Harvey, RP, Samuel, MS, Pajic, M, McGhee, EJ, Johnsson, AKE, Sansom, OJ, Welch, HCE, Morton, JP, Strathdee, D, Anderson, KI, and Timpson, P
- Abstract
The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time. Nobis et al. generated a RhoA-FRET biosensor mouse to characterize and quantify the spatiotemporal distribution of RhoA activity in native mammalian tissues in vivo during development and disease progression. They show that RhoA activity is tightly regulated during various normal biological processes and is co-opted in disease settings, such as invasive breast and pancreatic cancers.
- Published
- 2017
26. Intravital FRAP Imaging using an E-cadherin-GFP Mouse Reveals Disease- and Drug-Dependent Dynamic Regulation of Cell-Cell Junctions in Live Tissue
- Author
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Shane T. Grey, Claire Vennin, Lei Zhang, Sean C. Warren, Owen J. Sansom, Herbert Herzog, Stacey N. Walters, Saadia A. Karim, T.R. Jeffry Evans, Zahra Erami, Paul Timpson, Kendelle J. Murphy, Kurt I. Anderson, Andrew D. Campbell, David Gallego-Ortega, David R. Croucher, Astrid Magenau, Juliane P. Schwarz, Max Nobis, Shereen Kadir, Peter W. Gunning, Wilfred Leung, Agata Mrowinska, James R.W. Conway, Nadine Reischmann, David Herrmann, Morghan C. Lucas, Andrew M. K. Law, Ewan J. McGhee, Edna C. Hardeman, Jennifer P. Morton, Douglas Strathdee, Christopher J. Ormandy, and Rachel A. Ridgway
- Subjects
0301 basic medicine ,Resource ,p53 ,Cell ,pancreatic cancer ,Green Fluorescent Proteins ,Mice, Transgenic ,Biology ,Cell junction ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,cell adhesion and migration ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Mice ,Pancreatic cancer ,medicine ,Tumor Microenvironment ,Animals ,lcsh:QH301-705.5 ,Tumor microenvironment ,Cadherin ,Optical Imaging ,Cancer ,E-cadherin ,Neoplasms, Experimental ,0601 Biochemistry and Cell Biology, 1116 Medical Physiology ,medicine.disease ,Cadherins ,invasion and metastasis ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,Organ Specificity ,Src-kinase ,FRAP ,Kras ,intravital imaging ,Tumor Suppressor Protein p53 ,Pancreas - Abstract
Summary E-cadherin-mediated cell-cell junctions play a prominent role in maintaining the epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here we generated an E-cadherin-GFP mouse that enables intravital photobleaching and quantification of E-cadherin mobility in live tissue without affecting normal biology. We demonstrate the broad applications of this mouse by examining E-cadherin regulation in multiple tissues, including mammary, brain, liver, and kidney tissue, while specifically monitoring E-cadherin mobility during disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression. FRAP in the E-cadherin-GFP mouse, therefore, promises to be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments., Graphical Abstract, Highlights • The E-cadherin-GFP mouse allows in situ quantification of E-cadherin mobility • We monitored E-cadherin mobility during tissue homeostasis and disease development • Invasive pancreatic cancer driven by mutant Kras/p53 increases E-cadherin mobility • Dasatinib treatment reverts E-cadherin mobility and reinforces tumor cell junctions, Erami et al. generate an E-cadherin-GFP mouse to demonstrate real-time quantification of E-cadherin mobility using intravital photobleaching in a range of tissue types. They show that changes in E-cadherin mobility correlate with changes in cell junction integrity and invasiveness while demonstrating applications of the mouse for future drug discovery studies.
- Published
- 2015
27. A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts
- Author
-
Nobis, Max, primary, Herrmann, David, additional, Warren, Sean C., additional, Kadir, Shereen, additional, Leung, Wilfred, additional, Killen, Monica, additional, Magenau, Astrid, additional, Stevenson, David, additional, Lucas, Morghan C., additional, Reischmann, Nadine, additional, Vennin, Claire, additional, Conway, James R.W., additional, Boulghourjian, Alice, additional, Zaratzian, Anaiis, additional, Law, Andrew M., additional, Gallego-Ortega, David, additional, Ormandy, Christopher J., additional, Walters, Stacey N., additional, Grey, Shane T., additional, Bailey, Jacqueline, additional, Chtanova, Tatyana, additional, Quinn, Julian M.W., additional, Baldock, Paul A., additional, Croucher, Peter I., additional, Schwarz, Juliane P., additional, Mrowinska, Agata, additional, Zhang, Lei, additional, Herzog, Herbert, additional, Masedunskas, Andrius, additional, Hardeman, Edna C., additional, Gunning, Peter W., additional, del Monte-Nieto, Gonzalo, additional, Harvey, Richard P., additional, Samuel, Michael S., additional, Pajic, Marina, additional, McGhee, Ewan J., additional, Johnsson, Anna-Karin E., additional, Sansom, Owen J., additional, Welch, Heidi C.E., additional, Morton, Jennifer P., additional, Strathdee, Douglas, additional, Anderson, Kurt I., additional, and Timpson, Paul, additional
- Published
- 2017
- Full Text
- View/download PDF
28. Abstract PR07: A biosensor mouse to predict the dissociation and spread of pancreatic cancer
- Author
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Herrmann, David, primary, Erami, Zahra, additional, Warren, Sean, additional, Nobis, Max, additional, Magenau, Astrid, additional, Lucas, Morghan, additional, Vennin, Claire, additional, McGhee, Ewan J., additional, Leung, Wilfred, additional, Reischmann, Nadine, additional, Mrowinska, Agata, additional, Schwarz, Juliane P., additional, Kadir, Shereen, additional, Karim, Saadia A., additional, Campbell, Andrew D., additional, Gallego-Ortega, David, additional, Evans, Jeffry, additional, Sansom, Owen J., additional, Morton, Jennifer P., additional, Anderson, Kurt I., additional, and Timpson, Paul, additional
- Published
- 2017
- Full Text
- View/download PDF
29. Intravital FRAP Imaging using an E-cadherin-GFP Mouse Reveals Disease- and Drug-Dependent Dynamic Regulation of Cell-Cell Junctions in Live Tissue
- Author
-
Erami, Z, Herrmann, D, Warren, SC, Nobis, M, McGhee, EJ, Lucas, MC, Leung, W, Reischmann, N, Mrowinska, A, Schwarz, JP, Kadir, S, Conway, JRW, Vennin, C, Karim, SA, Campbell, AD, Gallego-Ortega, D, Magenau, A, Murphy, KJ, Ridgway, RA, Law, AM, Walters, SN, Grey, ST, Croucher, DR, Zhang, L, Herzog, H, Hardeman, EC, Gunning, PW, Ormandy, CJ, Evans, TRJ, Strathdee, D, Sansom, OJ, Morton, JP, Anderson, KI, Timpson, P, Erami, Z, Herrmann, D, Warren, SC, Nobis, M, McGhee, EJ, Lucas, MC, Leung, W, Reischmann, N, Mrowinska, A, Schwarz, JP, Kadir, S, Conway, JRW, Vennin, C, Karim, SA, Campbell, AD, Gallego-Ortega, D, Magenau, A, Murphy, KJ, Ridgway, RA, Law, AM, Walters, SN, Grey, ST, Croucher, DR, Zhang, L, Herzog, H, Hardeman, EC, Gunning, PW, Ormandy, CJ, Evans, TRJ, Strathdee, D, Sansom, OJ, Morton, JP, Anderson, KI, and Timpson, P
- Abstract
E-cadherin-mediated cell-cell junctions play a prominent role in maintaining the epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here we generated an E-cadherin-GFP mouse that enables intravital photobleaching and quantification of E-cadherin mobility in live tissue without affecting normal biology. We demonstrate the broad applications of this mouse by examining E-cadherin regulation in multiple tissues, including mammary, brain, liver, and kidney tissue, while specifically monitoring E-cadherin mobility during disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression. FRAP in the E-cadherin-GFP mouse, therefore, promises to be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments. Erami et al. generate an E-cadherin-GFP mouse to demonstrate real-time quantification of E-cadherin mobility using intravital photobleaching in a range of tissue types. They show that changes in E-cadherin mobility correlate with changes in cell junction integrity and invasiveness while demonstrating applications of the mouse for future drug discovery studies.
- Published
- 2016
30. Abstract PR07: A biosensor mouse to predict the dissociation and spread of pancreatic cancer
- Author
-
Morghan C. Lucas, Jennifer P. Morton, David Gallego-Ortega, Claire Vennin, Owen J. Sansom, Paul Timpson, Saadia A. Karim, Jeffry Evans, Nadine Reischmann, Zahra Erami, Kurt I. Anderson, Andrew D. Campbell, Sean C. Warren, Shereen Kadir, Juliane P. Schwarz, Max Nobis, Wilfred Leung, David Herrmann, Ewan J. McGhee, Astrid Magenau, and Agata Mrowinska
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Pancreatic tissue ,Liver and kidney ,Disease progression ,Biology ,medicine.disease ,medicine.disease_cause ,Metastasis ,03 medical and health sciences ,Drug treatment ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Pancreatic cancer ,Cancer research ,medicine ,KRAS ,Pancreas - Abstract
E-cadherin-mediated cell-cell junctions play a physical role in maintaining normal epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here, we have generated an E-cadherin-GFP(FRAP) biosensor mouse, which enables intravital photobleaching and quantification of E-cadherin mobility in live tissue, without affecting normal biology. We demonstrate using FRAP or FLIP, the broad applications of this mouse to examine E-cadherin regulation in multiple tissues including mammary, brain, liver and kidney, while specifically monitoring E-cadherin mobility during disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue, upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment, and reveal new insights into the dynamic remodeling of E-cadherin during in situ cancer progression. Photobleaching in the E-cadherin-GFP(FRAP) mouse correlate directly with epithelial integrity and mechanical strength making the biosensor mouse a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native micro-environments. This abstract is also being presented as Poster B23. Citation Format: David Herrmann, Zahra Erami, Sean Warren, Max Nobis, Astrid Magenau, Morghan Lucas, Claire Vennin, Ewan J. McGhee, Wilfred Leung, Nadine Reischmann, Agata Mrowinska, Juliane P. Schwarz, Shereen Kadir, Saadia A. Karim, Andrew D. Campbell, David Gallego-Ortega, Jeffry Evans, Owen J. Sansom, Jennifer P. Morton, Kurt I. Anderson, Paul Timpson. A biosensor mouse to predict the dissociation and spread of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr PR07.
- Published
- 2017
31. Intravital FRAP Imaging using an E-cadherin-GFP Mouse Reveals Disease- and Drug-Dependent Dynamic Regulation of Cell-Cell Junctions in Live Tissue
- Author
-
Erami, Zahra, primary, Herrmann, David, additional, Warren, Sean C., additional, Nobis, Max, additional, McGhee, Ewan J., additional, Lucas, Morghan C., additional, Leung, Wilfred, additional, Reischmann, Nadine, additional, Mrowinska, Agata, additional, Schwarz, Juliane P., additional, Kadir, Shereen, additional, Conway, James R.W., additional, Vennin, Claire, additional, Karim, Saadia A., additional, Campbell, Andrew D., additional, Gallego-Ortega, David, additional, Magenau, Astrid, additional, Murphy, Kendelle J., additional, Ridgway, Rachel A., additional, Law, Andrew M., additional, Walters, Stacey N., additional, Grey, Shane T., additional, Croucher, David R., additional, Zhang, Lei, additional, Herzog, Herbert, additional, Hardeman, Edna C., additional, Gunning, Peter W., additional, Ormandy, Christopher J., additional, Evans, T.R. Jeffry, additional, Strathdee, Douglas, additional, Sansom, Owen J., additional, Morton, Jennifer P., additional, Anderson, Kurt I., additional, and Timpson, Paul, additional
- Published
- 2016
- Full Text
- View/download PDF
32. Targeting mTOR dependency in pancreatic cancer
- Author
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Morran, DC, Wu, J, Jamieson, NB, Mrowinska, A, Kalna, G, Karim, SA, Au, AYM, Scarlett, CJ, Chang, DK, Pajak, MZ, Oien, KA, McKay, CJ, Carter, CR, Gillen, G, Champion, S, Pimlott, SL, Anderson, KI, Evans, TRJ, Grimmond, SM, Biankin, AV, Sansom, OJ, Morton, JP, Morran, DC, Wu, J, Jamieson, NB, Mrowinska, A, Kalna, G, Karim, SA, Au, AYM, Scarlett, CJ, Chang, DK, Pajak, MZ, Oien, KA, McKay, CJ, Carter, CR, Gillen, G, Champion, S, Pimlott, SL, Anderson, KI, Evans, TRJ, Grimmond, SM, Biankin, AV, Sansom, OJ, and Morton, JP
- Abstract
OBJECTIVE: Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease. DESIGN: Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of Kras(G12D)-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition. RESULTS: We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours. CONCLUSIONS: KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future.
- Published
- 2014
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