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Pancreatic Neoplasms: HELP
Articles by Saadia A. Karim
Based on 14 articles published since 2010
(Why 14 articles?)
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Between 2010 and 2020, Saadia Karim wrote the following 14 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article CSF1R 2018

Candido, Juliana B / Morton, Jennifer P / Bailey, Peter / Campbell, Andrew D / Karim, Saadia A / Jamieson, Thomas / Lapienyte, Laura / Gopinathan, Aarthi / Clark, William / McGhee, Ewan J / Wang, Jun / Escorcio-Correia, Monica / Zollinger, Raphael / Roshani, Rozita / Drew, Lisa / Rishi, Loveena / Arkell, Rebecca / Evans, T R Jeffry / Nixon, Colin / Jodrell, Duncan I / Wilkinson, Robert W / Biankin, Andrew V / Barry, Simon T / Balkwill, Frances R / Sansom, Owen J. ·Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. · Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. · Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. · Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. · Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK. · Bioscience, Oncology, iMED Biotech Unit, AstraZeneca, Boston, MA, USA. · MedImmune Ltd, Granta Park, Cambridge CB21 6GH, UK. · Bioscience, Oncology, iMED Biotech Unit, AstraZeneca, Cambridge, UK. · Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. Electronic address: o.sansom@beatson.gla.ac.uk. ·Cell Rep · Pubmed #29719257.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors.

2 Article Mutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma. 2018

Schofield, Heather K / Zeller, Jörg / Espinoza, Carlos / Halbrook, Christopher J / Del Vecchio, Annachiara / Magnuson, Brian / Fabo, Tania / Daylan, Ayse Ece Cali / Kovalenko, Ilya / Lee, Ho-Joon / Yan, Wei / Feng, Ying / Karim, Saadia A / Kremer, Daniel M / Kumar-Sinha, Chandan / Lyssiotis, Costas A / Ljungman, Mats / Morton, Jennifer P / Galbán, Stefanie / Fearon, Eric R / Pasca di Magliano, Marina. ·Department of Surgery. · Program in Cellular and Molecular Biology. · Medical Scientist Training Program. · Department of Internal Medicine. · Center for Molecular Imaging. · Department of Radiology. · Department of Molecular and Integrative Physiology, and. · Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA. · Harvard University, Cambridge, Massachusetts, USA. · Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom. · Department of Pathology. · Comprehensive Cancer Center. · Department of Radiation Oncology. · Department of Environmental Health Sciences. · Department of Human Genetics, and. · Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA. ·JCI Insight · Pubmed #29367463.

ABSTRACT: Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 is mutated in more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental in studies of the contribution of individual genes to carcinogenesis. Oncogenic Kras mutations occur early during pancreatic carcinogenesis and are considered an initiating event. In contrast, mutations in p53 occur later during tumor progression. In our model, we recapitulated the order of mutations of the human disease, with p53 mutation following expression of oncogenic Kras. Further, using an inducible and reversible expression allele for mutant p53, we inactivated its expression at different stages of carcinogenesis. Notably, the function of mutant p53 changes at different stages of carcinogenesis. Our work establishes a requirement for mutant p53 for the formation and maintenance of pancreatic cancer precursor lesions. In tumors, mutant p53 becomes dispensable for growth. However, it maintains the altered metabolism that characterizes pancreatic cancer and mediates its malignant potential. Further, mutant p53 promotes epithelial-mesenchymal transition (EMT) and cancer cell invasion. This work generates new mouse models that mimic human pancreatic cancer and expands our understanding of the role of p53 mutation, common in the majority of human malignancies.

3 Article Substrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells. 2017

Lachowski, Dariusz / Cortes, Ernesto / Pink, Daniel / Chronopoulos, Antonios / Karim, Saadia A / P Morton, Jennifer / Del Río Hernández, Armando E. ·Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, SW7 2AZ, United Kingdom. · Pancreatic Cancer Research Team, CRUK Beatson Institute, Glasgow, G61 1BD, United Kingdom. · Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, SW7 2AZ, United Kingdom. a.del-rio-hernandez@imperial.ac.uk. ·Sci Rep · Pubmed #28566691.

ABSTRACT: Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive malignancy characterised by the presence of extensive desmoplasia, thought to be responsible for the poor response of patients to systemic therapies. Pancreatic stellate cells (PSCs) are key mediators in the production of this fibrotic stroma, upon activation transitioning to a myofibroblast-like, high matrix secreting phenotype. Given their importance in disease progression, characterisation of PSC activation has been extensive, however one aspect that has been overlooked is the mechano-sensing properties of the cell. Here, through the use of a physiomimetic system that recapitulates the mechanical microenvironment found within healthy and fibrotic pancreas, we demonstrate that matrix stiffness regulates activation and mechanotaxis in PSCs. We show the ability of PSCs to undergo phenotypic transition solely as a result of changes in extracellular matrix stiffness, whilst observing the ability of PSCs to durotactically respond to stiffness variations within their local environment. Our findings implicate the mechanical microenvironment as a potent contributor to PDAC progression and survival via induction of PSC activation and fibrosis, suggesting that direct mechanical reprogramming of PSCs may be a viable alternative in the treatment of this lethal disease.

4 Article mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer. 2016

Driscoll, David R / Karim, Saadia A / Sano, Makoto / Gay, David M / Jacob, Wright / Yu, Jun / Mizukami, Yusuke / Gopinathan, Aarthi / Jodrell, Duncan I / Evans, T R Jeffry / Bardeesy, Nabeel / Hall, Michael N / Quattrochi, Brian J / Klimstra, David S / Barry, Simon T / Sansom, Owen J / Lewis, Brian C / Morton, Jennifer P. ·Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts. · CRUK Beatson Institute, Glasgow, United Kingdom. · Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan. · Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. · Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. · CRUK Cambridge Institute, Cambridge, United Kingdom. · Biozentrum, University of Basel, Basel, Switzerland. · Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. · AstraZeneca, Macclesfield, United Kingdom. · CRUK Beatson Institute, Glasgow, United Kingdom. o.sansom@beatson.gla.ac.uk Brian.Lewis@umassmed.edu. · Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts. o.sansom@beatson.gla.ac.uk Brian.Lewis@umassmed.edu. · Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts. ·Cancer Res · Pubmed #27758884.

ABSTRACT: mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis. Whereas previous studies showed most pancreatic tumors were insensitive to rapamycin, treatment with a dual mTORC1/2 inhibitor strongly suppressed tumorigenesis. In late-stage tumor-bearing mice, combined mTORC1/2 and PI3K inhibition significantly increased survival. Thus, targeting mTOR may be a potential therapeutic strategy in pancreatic cancer. Cancer Res; 76(23); 6911-23. ©2016 AACR.

5 Article CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. 2016

Steele, Colin W / Karim, Saadia A / Leach, Joshua D G / Bailey, Peter / Upstill-Goddard, Rosanna / Rishi, Loveena / Foth, Mona / Bryson, Sheila / McDaid, Karen / Wilson, Zena / Eberlein, Catherine / Candido, Juliana B / Clarke, Mairi / Nixon, Colin / Connelly, John / Jamieson, Nigel / Carter, C Ross / Balkwill, Frances / Chang, David K / Evans, T R Jeffry / Strathdee, Douglas / Biankin, Andrew V / Nibbs, Robert J B / Barry, Simon T / Sansom, Owen J / Morton, Jennifer P. ·Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. · Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK. · Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK. · Centre for Cancer and Inflammation, Barts Cancer Institute, London EC1M 6BQ, UK. · Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8QQ UK. · Department of Surgery, Glasgow Royal Infirmary, Glasgow G4 0SF, UK. · Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK. · Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK. Electronic address: o.sansom@beatson.gla.ac.uk. ·Cancer Cell · Pubmed #27265504.

ABSTRACT: CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that CXCR2 signaling is upregulated in human pancreatic cancer, predominantly in neutrophil/myeloid-derived suppressor cells, but rarely in tumor cells. Genetic ablation or inhibition of CXCR2 abrogated metastasis, but only inhibition slowed tumorigenesis. Depletion of neutrophils/myeloid-derived suppressor cells also suppressed metastasis suggesting a key role for CXCR2 in establishing and maintaining the metastatic niche. Importantly, loss or inhibition of CXCR2 improved T cell entry, and combined inhibition of CXCR2 and PD1 in mice with established disease significantly extended survival. We show that CXCR2 signaling in the myeloid compartment can promote pancreatic tumorigenesis and is required for pancreatic cancer metastasis, making it an excellent therapeutic target.

6 Article Genomic analyses identify molecular subtypes of pancreatic cancer. 2016

Bailey, Peter / Chang, David K / Nones, Katia / Johns, Amber L / Patch, Ann-Marie / Gingras, Marie-Claude / Miller, David K / Christ, Angelika N / Bruxner, Tim J C / Quinn, Michael C / Nourse, Craig / Murtaugh, L Charles / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourbakhsh, Ehsan / Wani, Shivangi / Fink, Lynn / Holmes, Oliver / Chin, Venessa / Anderson, Matthew J / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Xu, Qinying / Wilson, Peter J / Cloonan, Nicole / Kassahn, Karin S / Taylor, Darrin / Quek, Kelly / Robertson, Alan / Pantano, Lorena / Mincarelli, Laura / Sanchez, Luis N / Evers, Lisa / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Colvin, Emily K / Nagrial, Adnan M / Humphrey, Emily S / Chantrill, Lorraine A / Mawson, Amanda / Humphris, Jeremy / Chou, Angela / Pajic, Marina / Scarlett, Christopher J / Pinho, Andreia V / Giry-Laterriere, Marc / Rooman, Ilse / Samra, Jaswinder S / Kench, James G / Lovell, Jessica A / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Moran-Jones, Kim / Jamieson, Nigel B / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Grützmann, Robert / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Corbo, Vincenzo / Bassi, Claudio / Rusev, Borislav / Capelli, Paola / Salvia, Roberto / Tortora, Giampaolo / Mukhopadhyay, Debabrata / Petersen, Gloria M / Anonymous2640859 / Munzy, Donna M / Fisher, William E / Karim, Saadia A / Eshleman, James R / Hruban, Ralph H / Pilarsky, Christian / Morton, Jennifer P / Sansom, Owen J / Scarpa, Aldo / Musgrove, Elizabeth A / Bailey, Ulla-Maja Hagbo / Hofmann, Oliver / Sutherland, Robert L / Wheeler, David A / Gill, Anthony J / Gibbs, Richard A / Pearson, John V / Waddell, Nicola / Biankin, Andrew V / Grimmond, Sean M. ·Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. · Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA. · Genetic and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia. · School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia. · Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA. · Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales 2560, Australia. · Department of Pathology. SydPath, St Vincent's Hospital, Sydney, NSW 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia. · School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. · Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · University of Sydney, Sydney, New South Wales 2006, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown New South Wales 2050, Australia. · School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia. · Fiona Stanley Hospital, Robin Warren Drive, Murdoch, Western Australia 6150, Australia. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. · Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. · School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. · Department of Pathology, Southern General Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. · GGC Bio-repository, Pathology Department, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TY, UK. · Department of Surgery, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany. · Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas 77030, USA. · The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Medical Oncology, Comprehensive Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · Mayo Clinic, Rochester, Minnesota 55905, USA. · Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. · Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. · Institute for Cancer Science, University of Glasgow, Glasgow G12 8QQ, UK. · University of Melbourne, Parkville, Victoria 3010, Australia. ·Nature · Pubmed #26909576.

ABSTRACT: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

7 Article Intravital FRAP Imaging using an E-cadherin-GFP Mouse Reveals Disease- and Drug-Dependent Dynamic Regulation of Cell-Cell Junctions in Live Tissue. 2016

Erami, Zahra / Herrmann, David / Warren, Sean C / Nobis, Max / McGhee, Ewan J / Lucas, Morghan C / Leung, Wilfred / Reischmann, Nadine / Mrowinska, Agata / Schwarz, Juliane P / Kadir, Shereen / Conway, James R W / Vennin, Claire / Karim, Saadia A / Campbell, Andrew D / Gallego-Ortega, David / Magenau, Astrid / Murphy, Kendelle J / Ridgway, Rachel A / Law, Andrew M / Walters, Stacey N / Grey, Shane T / Croucher, David R / Zhang, Lei / Herzog, Herbert / Hardeman, Edna C / Gunning, Peter W / Ormandy, Christopher J / Evans, T R Jeffry / Strathdee, Douglas / Sansom, Owen J / Morton, Jennifer P / Anderson, Kurt I / Timpson, Paul. ·Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia. · Neuromuscular and Regenerative Medicine Unit, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia. · Oncology Research Unit, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia. · Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK. Electronic address: k.anderson@beatson.gla.ac.uk. · The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia. Electronic address: p.timpson@garvan.org.au. ·Cell Rep · Pubmed #26725115.

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.

8 Article Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. 2015

Miller, Bryan W / Morton, Jennifer P / Pinese, Mark / Saturno, Grazia / Jamieson, Nigel B / McGhee, Ewan / Timpson, Paul / Leach, Joshua / McGarry, Lynn / Shanks, Emma / Bailey, Peter / Chang, David / Oien, Karin / Karim, Saadia / Au, Amy / Steele, Colin / Carter, Christopher Ross / McKay, Colin / Anderson, Kurt / Evans, Thomas R Jeffry / Marais, Richard / Springer, Caroline / Biankin, Andrew / Erler, Janine T / Sansom, Owen J. ·Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK. · The Garvan Institute of Medical Research, Sydney, NSW, Australia. · Cancer Research UK Manchester Institute, Withington Manchester, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Institute of Cancer Sciences University of Glasgow Garscube Estate, Glasgow, UK. · Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK Institute of Cancer Sciences University of Glasgow Garscube Estate, Glasgow, UK. · Institute of Cancer Research, London, UK. · Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen (UCPH), Denmark janine.erler@bric.ku.dk o.sansom@beatson.gla.ac.uk. · Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK janine.erler@bric.ku.dk o.sansom@beatson.gla.ac.uk. ·EMBO Mol Med · Pubmed #26077591.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1-Cre Kras(G12D/+) Trp53(R172H/+) (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor-free survival in KPC mice with early-stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease.

9 Article Targeting mTOR dependency in pancreatic cancer. 2014

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 / Anonymous6310790 / 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 / Morton, Jennifer P. ·CRUK Beatson Institute, Glasgow, UK. · The Kinghorn Cancer Centre and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · School of Environmental & Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia. · The Kinghorn Cancer Centre and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Liverpool, New South Wales, Australia The Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · CRUK Beatson Institute, Glasgow, UK Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. · West of Scotland PET Centre, Gartnavel General Hospital, Glasgow, UK. · West of Scotland Radionuclide Dispensary, NHS Greater Glasgow and Clyde, Glasgow, UK. · The Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, Queensland, Australia. ·Gut · Pubmed #24717934.

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.

10 Article Fascin is regulated by slug, promotes progression of pancreatic cancer in mice, and is associated with patient outcomes. 2014

Li, Ang / Morton, Jennifer P / Ma, YaFeng / Karim, Saadia A / Zhou, Yan / Faller, William J / Woodham, Emma F / Morris, Hayley T / Stevenson, Richard P / Juin, Amelie / Jamieson, Nigel B / MacKay, Colin J / Carter, C Ross / Leung, Hing Y / Yamashiro, Shigeko / Blyth, Karen / Sansom, Owen J / Machesky, Laura M. ·CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. · Department of Surgery, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey. · CRUK Beatson Institute for Cancer Research, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. Electronic address: l.machesky@beatson.gla.ac.uk. ·Gastroenterology · Pubmed #24462734.

ABSTRACT: BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is often lethal because it is highly invasive and metastasizes rapidly. The actin-bundling protein fascin has been identified as a biomarker of invasive and advanced PDAC and regulates cell migration and invasion in vitro. We investigated fascin expression and its role in PDAC progression in mice. METHODS: We used KRas(G12D) p53(R172H) Pdx1-Cre (KPC) mice to investigate the effects of fascin deficiency on development of pancreatic intraepithelial neoplasia (PanIn), PDAC, and metastasis. We measured levels of fascin in PDAC cell lines and 122 human resected PDAC samples, along with normal ductal and acinar tissues; we associated levels with patient outcomes. RESULTS: Pancreatic ducts and acini from control mice and early-stage PanINs from KPC mice were negative for fascin, but approximately 6% of PanIN3 and 100% of PDAC expressed fascin. Fascin-deficient KRas(G12D) p53(R172H) Pdx1-Cre mice had longer survival times, delayed onset of PDAC, and a lower PDAC tumor burdens than KPC mice; loss of fascin did not affect invasion of PDAC into bowel or peritoneum in mice. Levels of slug and fascin correlated in PDAC cells; slug was found to regulate transcription of Fascin along with the epithelial-mesenchymal transition. In PDAC cell lines and cells from mice, fascin concentrated in filopodia and was required for their assembly and turnover. Fascin promoted intercalation of filopodia into mesothelial cell layers and cell invasion. Nearly all human PDAC samples expressed fascin, and higher fascin histoscores correlated with poor outcomes, vascular invasion, and time to recurrence. CONCLUSIONS: The actin-bundling protein fascin is regulated by slug and involved in late-stage PanIN and PDAC formation in mice. Fascin appears to promote formation of filopodia and invasive activities of PDAC cells. Its levels in human PDAC correlate with outcomes and time to recurrence, indicating it might be a marker or therapeutic target for pancreatic cancer.

11 Article Intravital FLIM-FRET imaging reveals dasatinib-induced spatial control of src in pancreatic cancer. 2013

Nobis, Max / McGhee, Ewan J / Morton, Jennifer P / Schwarz, Juliane P / Karim, Saadia A / Quinn, Jean / Edward, Mike / Campbell, Andrew D / McGarry, Lynn C / Evans, T R Jeffry / Brunton, Valerie G / Frame, Margaret C / Carragher, Neil O / Wang, Yingxiao / Sansom, Owen J / Timpson, Paul / Anderson, Kurt I. ·The Beatson Institute for Cancer Research, Glasgow; Section of Dermatology, School of Medicine, University of Glasgow, Glasgow, UK. ·Cancer Res · Pubmed #23749641.

ABSTRACT: Cancer invasion and metastasis occur in a complex three-dimensional (3D) environment, with reciprocal feedback from the surrounding host tissue and vasculature-governing behavior. In this study, we used a novel intravital method that revealed spatiotemporal regulation of Src activity in response to the anti-invasive Src inhibitor dasatinib. A fluorescence lifetime imaging microscopy-fluorescence resonance energy transfer (FLIM-FRET) Src biosensor was used to monitor drug-targeting efficacy in a transgenic p53-mutant mouse model of pancreatic cancer. In contrast to conventional techniques, FLIM-FRET analysis allowed for accurate, time-dependent, live monitoring of drug efficacy and clearance in live tumors. In 3D organotypic cultures, we showed that a spatially distinct gradient of Src activity exists within invading tumor cells, governed by the depth of penetration into complex matrices. In parallel, this gradient was also found to exist within live tumors, where Src activity is enhanced at the invasive border relative to the tumor cortex. Upon treatment with dasatinib, we observed a switch in activity at the invasive borders, correlating with impaired metastatic capacity in vivo. Src regulation was governed by the proximity of cells to the host vasculature, as cells distal to the vasculature were regulated differentially in response to drug treatment compared with cells proximal to the vasculature. Overall, our results in live tumors revealed that a threshold of drug penetrance exists in vivo and that this can be used to map areas of poor drug-targeting efficiency within specific tumor microenvironments. We propose that using FLIM-FRET in this capacity could provide a useful preclinical tool in animal models before clinical translation.

12 Article Spatial regulation of RhoA activity during pancreatic cancer cell invasion driven by mutant p53. 2011

Timpson, Paul / McGhee, Ewan J / Morton, Jennifer P / von Kriegsheim, Alex / Schwarz, Juliane P / Karim, Saadia A / Doyle, Brendan / Quinn, Jean A / Carragher, Neil O / Edward, Mike / Olson, Michael F / Frame, Margaret C / Brunton, Valerie G / Sansom, Owen J / Anderson, Kurt I. ·The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. p.timpson@beatson.gla.ac.uk ·Cancer Res · Pubmed #21266354.

ABSTRACT: The ability to observe changes in molecular behavior during cancer cell invasion in vivo remains a major challenge to our understanding of the metastatic process. Here, we demonstrate for the first time, an analysis of RhoA activity at a subcellular level using FLIM-FRET (fluorescence lifetime imaging microscopy-fluorescence resonance energy transfer) imaging in a live animal model of pancreatic cancer. In invasive mouse pancreatic ductal adenocarcinoma (PDAC) cells driven by mutant p53 (p53(R172H)), we observed a discrete fraction of high RhoA activity at both the leading edge and rear of cells in vivo which was absent in two-dimensional in vitro cultures. Notably, this pool of active RhoA was absent in noninvasive p53(fl) knockout PDAC cells, correlating with their poor invasive potential in vivo. We used dasatanib, a clinically approved anti-invasive agent that is active in this model, to illustrate the functional importance of spatially regulated RhoA. Dasatanib inhibited the activity of RhoA at the poles of p53(R172H) cells in vivo and this effect was independent of basal RhoA activity within the cell body. Taken together, quantitative in vivo fluorescence lifetime imaging illustrated that RhoA is not only necessary for invasion, but also that subcellular spatial regulation of RhoA activity, as opposed to its global activity, is likely to govern invasion efficiency in vivo. Our findings reveal the utility of FLIM-FRET in analyzing dynamic biomarkers during drug treatment in living animals, and they also show how discrete intracellular molecular pools might be differentially manipulated by future anti-invasive therapies.

13 Article LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. 2010

Morton, Jennifer P / Jamieson, Nigel B / Karim, Saadia A / Athineos, Dimitris / Ridgway, Rachel A / Nixon, Colin / McKay, Colin J / Carter, Ross / Brunton, Valerie G / Frame, Margaret C / Ashworth, Alan / Oien, Karin A / Evans, T R Jeffry / Sansom, Owen J. ·Beatson Institute for Cancer Research, Garscube Estate, Glasgow, UK. ·Gastroenterology · Pubmed #20452353.

ABSTRACT: BACKGROUND & AIMS: Patients carrying germline mutations of LKB1 have an increased risk of pancreatic cancer; however, it is unclear whether down-regulation of LKB1 is an important event in sporadic pancreatic cancer. In this study, we aimed to investigate the impact of LKB1 down-regulation for pancreatic cancer in mouse and human and to elucidate the mechanism by which Lkb1 deregulation contributes to this disease. METHODS: We first investigated the consequences of Lkb1 deficiency in a genetically modified mouse model of pancreatic cancer, both in terms of disease progression and at the molecular level. To test the relevance of our findings to human pancreatic cancer, we investigated levels of LKB1 and its potential targets in human pancreatic cancer. RESULTS: We definitively show that Lkb1 haploinsufficiency can cooperate with oncogenic KrasG12D to cause pancreatic ductal adenocarcinoma (PDAC) in the mouse. Mechanistically, this was associated with decreased p53/p21-dependent growth arrest. Haploinsufficiency for p21 (Cdkn1a) also synergizes with KrasG12D to drive PDAC in the mouse. We also found that levels of LKB1 expression were decreased in around 20% of human PDAC and significantly correlated with low levels of p21 and a poor prognosis. Remarkably, all tumors that had low levels of LKB1 had low levels of p21, and these tumors did not express mutant p53. CONCLUSIONS: We have identified a novel LKB1-p21 axis that suppresses PDAC following Kras mutation in vivo. Down-regulation of LKB1 may therefore serve as an alternative to p53 mutation to drive pancreatic cancer in vivo.

14 Article Dasatinib inhibits the development of metastases in a mouse model of pancreatic ductal adenocarcinoma. 2010

Morton, Jennifer P / Karim, Saadia A / Graham, Kathryn / Timpson, Paul / Jamieson, Nigel / Athineos, Dimitris / Doyle, Brendan / McKay, Colin / Heung, Man-Yeung / Oien, Karin A / Frame, Margaret C / Evans, T R Jeffry / Sansom, Owen J / Brunton, Valerie G. ·Beatson Institute for Cancer Research, Glasgow, United Kingdom. ·Gastroenterology · Pubmed #20303350.

ABSTRACT: BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive and metastatic disease for which conventional treatments are of limited efficacy. A number of agents in development are potential anti-invasive and antimetastatic agents, including the Src kinase inhibitor dasatinib. The aim of this study was to assess the importance of Src in human PDAC and to use a genetically engineered mouse model of PDAC to determine the effects of dasatinib on PDAC progression. METHODS: Src expression and activity was measured by immunohistochemistry in 114 human PDACs. Targeting expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas results in the formation of invasive and metastatic PDAC. These mice were treated with dasatinib, and disease progression monitored. Cell lines were derived from mouse PDACs, and in vitro effects of dasatinib assessed. RESULTS: Src expression and activity were up-regulated in human PDAC and this correlated with reduced survival. Dasatinib inhibited the migration and invasion of PDAC cell lines, although no effects on proliferation were seen at concentrations that inhibited Src kinase activity. In addition, dasatinib significantly inhibited the development of metastases in Pdx1-Cre, Z/EGFP, LSL-Kras(G12D/+), LSL-Trp53(R172H/+) mice. However, there was no survival advantage in the dasatinib-treated animals owing to continued growth of the primary tumor. CONCLUSIONS: This study confirms the importance of Src in human PDAC and shows the usefulness of a genetically engineered mouse model of PDAC for assessing the activity of potential antimetastatic agents and suggests that dasatinib should be evaluated further as monotherapy after resection of localized invasive PDAC.