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Pancreatic Neoplasms: HELP
Articles by Jennifer P. Morton
Based on 46 articles published since 2010
(Why 46 articles?)
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Between 2010 and 2020, J. Morton wrote the following 46 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial CXCR2 inhibition in pancreatic cancer: opportunities for immunotherapy? 2017

Morton, Jennifer P / Sansom, Owen J. ·Cancer Research UK Beatson Institute, Switchback Rd, Glasgow, G61 1BD, UK. · Institute of Cancer Sciences, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK. ·Immunotherapy · Pubmed #28000523.

ABSTRACT: -- No abstract --

2 Editorial Timing is everything: Brca2 and p53 mutations in pancreatic cancer. 2011

Morton, Jennifer P / Steele, Colin W / Sansom, Owen J. · ·Gastroenterology · Pubmed #21352873.

ABSTRACT: -- No abstract --

3 Review Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine. 2019

Conway, James Rw / Herrmann, David / Evans, Tr Jeffry / Morton, Jennifer P / Timpson, Paul. ·Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Cancer Division, Sydney, New South Wales, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. · Cancer Department, Cancer Research UK Beatson Institute, Glasgow, UK. · Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. ·Gut · Pubmed #30396902.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly solid tumours. This is due to a generally late-stage diagnosis of a primarily treatment-refractory disease. Several large-scale sequencing and mass spectrometry approaches have identified key drivers of this disease and in doing so highlighted the vast heterogeneity of lower frequency mutations that make clinical trials of targeted agents in unselected patients increasingly futile. There is a clear need for improved biomarkers to guide effective targeted therapies, with biomarker-driven clinical trials for personalised medicine becoming increasingly common in several cancers. Interestingly, many of the aberrant signalling pathways in PDAC rely on downstream signal transduction through the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways, which has led to the development of several approaches to target these key regulators, primarily as combination therapies. The following review discusses the trend of PDAC therapy towards molecular subtyping for biomarker-driven personalised therapies, highlighting the key pathways under investigation and their relationship to the PI3K pathway.

4 Review Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer. 2018

Vennin, Claire / Murphy, Kendelle J / Morton, Jennifer P / Cox, Thomas R / Pajic, Marina / Timpson, Paul. ·The Garvan Institute of Medical Research, Sydney, New South Wales, Australia; The Kinghorn Cancer Center, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. · Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow, Scotland, United Kingdom. · The Garvan Institute of Medical Research, Sydney, New South Wales, Australia; The Kinghorn Cancer Center, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. Electronic address: m.pajic@garvan.org.au. · The Garvan Institute of Medical Research, Sydney, New South Wales, Australia; The Kinghorn Cancer Center, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. Electronic address: p.timpson@garvan.org.au. ·Gastroenterology · Pubmed #29287624.

ABSTRACT: Pancreatic cancer is accompanied by a fibrotic reaction that alters interactions between tumor cells and the stroma to promote tumor progression. Consequently, strategies to target the tumor stroma might be used to treat patients with pancreatic cancer. We review recently developed approaches for reshaping the pancreatic tumor stroma and discuss how these might improve patient outcomes. We also describe relationships between the pancreatic tumor extracellular matrix, the vasculature, the immune system, and metabolism, and discuss the implications for the development of stromal compartment-specific therapies.

5 Review GEMMs as preclinical models for testing pancreatic cancer therapies. 2015

Gopinathan, Aarthi / Morton, Jennifer P / Jodrell, Duncan I / Sansom, Owen J. ·Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK Aarthi.Gopinathan@cruk.cam.ac.uk o.sansom@beatson.gla.ac.uk. · Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK. · Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK. · Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK Aarthi.Gopinathan@cruk.cam.ac.uk o.sansom@beatson.gla.ac.uk. ·Dis Model Mech · Pubmed #26438692.

ABSTRACT: Pancreatic ductal adenocarcinoma is the most common form of pancreatic tumour, with a very limited survival rate and currently no available disease-modifying treatments. Despite recent advances in the production of genetically engineered mouse models (GEMMs), the development of new therapies for pancreatic cancer is still hampered by a lack of reliable and predictive preclinical animal models for this disease. Preclinical models are vitally important for assessing therapies in the first stages of the drug development pipeline, prior to their transition to the clinical arena. GEMMs carry mutations in genes that are associated with specific human diseases and they can thus accurately mimic the genetic, phenotypic and physiological aspects of human pathologies. Here, we discuss different GEMMs of human pancreatic cancer, with a focus on the Lox-Stop-Lox (LSL)-Kras(G12D); LSL-Trp53(R172H); Pdx1-cre (KPC) model, one of the most widely used preclinical models for this disease. We describe its application in preclinical research, highlighting its advantages and disadvantages, its potential for predicting clinical outcomes in humans and the factors that can affect such outcomes, and, finally, future developments that could advance the discovery of new therapies for pancreatic cancer.

6 Review Exploiting inflammation for therapeutic gain in pancreatic cancer. 2013

Steele, C W / Jamieson, N B / Evans, T R J / McKay, C J / Sansom, O J / Morton, J P / Carter, C R. ·The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK. ·Br J Cancer · Pubmed #23385734.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC.

7 Article Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism. 2019

Bott, Alex J / Shen, Jianliang / Tonelli, Claudia / Zhan, Le / Sivaram, Nithya / Jiang, Ya-Ping / Yu, Xufen / Bhatt, Vrushank / Chiles, Eric / Zhong, Hua / Maimouni, Sara / Dai, Weiwei / Velasquez, Stephani / Pan, Ji-An / Muthalagu, Nathiya / Morton, Jennifer / Anthony, Tracy G / Feng, Hui / Lamers, Wouter H / Murphy, Daniel J / Guo, Jessie Yanxiang / Jin, Jian / Crawford, Howard C / Zhang, Lanjing / White, Eileen / Lin, Richard Z / Su, Xiaoyang / Tuveson, David A / Zong, Wei-Xing. ·Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA; Genetics Graduate Program, Stony Brook University, Stony Brook, NY 07794, USA. · Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. · Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA. · Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA; Northport VA Medical Center, Northport, NY 11768, USA. · Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. · Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. · CRUK Beatson Institute, Glasgow G61 1BD, UK. · Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA. · Departments of Pharmacology and Medicine, Section of Hematology and Medical Oncology, Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, USA. · Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. · CRUK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK. · Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. · Departments of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA; Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA. · Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA. Electronic address: zongwx@rutgers.edu. ·Cell Rep · Pubmed #31665640.

ABSTRACT: Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-ketoglutarate (aKG) to fuel the tricarboxylic acid (TCA) cycle. Supporting this notion, aKG supplementation can restore growth/survival of glutamine-deprived cells. However, pancreatic cancers are often poorly vascularized and limited in glutamine supply, in alignment with recent concerns on the significance of glutaminolysis in pancreatic cancer. Here, we show that aKG-mediated rescue of glutamine-deprived pancreatic ductal carcinoma (PDAC) cells requires glutamate ammonia ligase (GLUL), the enzyme responsible for de novo glutamine synthesis. GLUL-deficient PDAC cells are capable of the TCA cycle but defective in aKG-coupled glutamine biosynthesis and subsequent nitrogen anabolic processes. Importantly, GLUL expression is elevated in pancreatic cancer patient samples and in mouse PDAC models. GLUL ablation suppresses the development of Kras

8 Article CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. 2019

Vennin, Claire / Mélénec, Pauline / Rouet, Romain / Nobis, Max / Cazet, Aurélie S / Murphy, Kendelle J / Herrmann, David / Reed, Daniel A / Lucas, Morghan C / Warren, Sean C / Elgundi, Zehra / Pinese, Mark / Kalna, Gabriella / Roden, Daniel / Samuel, Monisha / Zaratzian, Anaiis / Grey, Shane T / Da Silva, Andrew / Leung, Wilfred / Anonymous561018 / Mathivanan, Suresh / Wang, Yingxiao / Braithwaite, Anthony W / Christ, Daniel / Benda, Ales / Parkin, Ashleigh / Phillips, Phoebe A / Whitelock, John M / Gill, Anthony J / Sansom, Owen J / Croucher, David R / Parker, Benjamin L / Pajic, Marina / Morton, Jennifer P / Cox, Thomas R / Timpson, Paul. ·The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, 2010, Australia. · Molecular Pathology department, the Netherlands Cancer Institute, Amsterdam, 1066CX, the Netherlands. · Graduate school of Biomedical Engineering, University of New South Wales Sydney, Sydney, NSW, 2052, Australia. · Cancer Research UK Beatson Institute, Glasgow Scotland, G61 BD, UK. · Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, VIC, 3086, Australia. · Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. · Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, CA, 92121, USA. · Children's Medical Research Institute, University of Sydney, Sydney, NSW, 2006, Australia. · Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, 9054, New Zealand. · Maurice Wilkins Centre, University of Otago, Dunedin, 9054, New Zealand. · Biomedical imaging facility, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia. · Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia. · Australian Centre for Nanomedicine, University of New South Wales, Sydney, NSW, 2052, Australia. · Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia. · NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, NSW, 2065, Australia. · Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, 2065, Australia. · Schools of Life and Environmental Sciences, the Charles Perkin Centre, the University of Sydney, Sydney, NSW, 2006, Australia. · The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. t.cox@garvan.org.au. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, 2010, Australia. t.cox@garvan.org.au. · The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. p.timpson@garvan.org.au. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, 2010, Australia. p.timpson@garvan.org.au. ·Nat Commun · Pubmed #31406163.

ABSTRACT: Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.

9 Article Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer. 2019

Halbrook, Christopher J / Pontious, Corbin / Kovalenko, Ilya / Lapienyte, Laura / Dreyer, Stephan / Lee, Ho-Joon / Thurston, Galloway / Zhang, Yaqing / Lazarus, Jenny / Sajjakulnukit, Peter / Hong, Hanna S / Kremer, Daniel M / Nelson, Barbara S / Kemp, Samantha / Zhang, Li / Chang, David / Biankin, Andrew / Shi, Jiaqi / Frankel, Timothy L / Crawford, Howard C / Morton, Jennifer P / Pasca di Magliano, Marina / Lyssiotis, Costas A. ·Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. · Cancer Research UK, Beatson Institute, Glasgow G61 1BD, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G61 1QH, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. · University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA. · Cancer Research UK, Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: clyssiot@med.umich.edu. ·Cell Metab · Pubmed #30827862.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant infiltration of tumor-associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, a frontline chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate that macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Together, these findings provide insights into the role of macrophages in pancreatic cancer therapy and have potential to inform the design of future treatments. Additionally, we report that pyrimidine release is a general function of alternatively activated macrophage cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.

10 Article Activation of PP2A and Inhibition of mTOR Synergistically Reduce MYC Signaling and Decrease Tumor Growth in Pancreatic Ductal Adenocarcinoma. 2019

Allen-Petersen, Brittany L / Risom, Tyler / Feng, Zipei / Wang, Zhiping / Jenny, Zina P / Thoma, Mary C / Pelz, Katherine R / Morton, Jennifer P / Sansom, Owen J / Lopez, Charles D / Sheppard, Brett / Christensen, Dale J / Ohlmeyer, Michael / Narla, Goutham / Sears, Rosalie C. ·Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon. · Department of Cell, Developmental & Cancer Biology, Oregon Health and Science University, Portland, Oregon. · CRUK Beatson Institute, Glasgow, Scotland, United Kingdom. · Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Department of Hematology and Oncology, Oregon Health and Science University, Portland, Oregon. · Department of Surgery, Oregon Health and Science University, Portland, Oregon. · Oncotide Pharmaceuticals, Inc., Research Triangle Park, North Carolina. · Icahn School of Medicine at Mount Sinai, New York, New York. · School of Medicine, Case Western Reserve University, Cleveland, Ohio. · Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon. searsr@ohsu.edu. ·Cancer Res · Pubmed #30389701.

ABSTRACT: In cancer, kinases are often activated and phosphatases suppressed, leading to aberrant activation of signaling pathways driving cellular proliferation, survival, and therapeutic resistance. Although pancreatic ductal adenocarcinoma (PDA) has historically been refractory to kinase inhibition, therapeutic activation of phosphatases is emerging as a promising strategy to restore balance to these hyperactive signaling cascades. In this study, we hypothesized that phosphatase activation combined with kinase inhibition could deplete oncogenic survival signals to reduce tumor growth. We screened PDA cell lines for kinase inhibitors that could synergize with activation of protein phosphatase 2A (PP2A), a tumor suppressor phosphatase, and determined that activation of PP2A and inhibition of mTOR synergistically increase apoptosis and reduce oncogenic phenotypes

11 Article Removing physiological motion from intravital and clinical functional imaging data. 2018

Warren, Sean C / Nobis, Max / Magenau, Astrid / Mohammed, Yousuf H / Herrmann, David / Moran, Imogen / Vennin, Claire / Conway, James Rw / Mélénec, Pauline / Cox, Thomas R / Wang, Yingxiao / Morton, Jennifer P / Welch, Heidi Ce / Strathdee, Douglas / Anderson, Kurt I / Phan, Tri Giang / Roberts, Michael S / Timpson, Paul. ·Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia. · Therapeutics Research Centre, Diamantina Institute, Faculty of Medicine, University of Queensland, Woolloongabba, Australia. · Immunology Division, Garvan Institute of Medical Research, Sydney, Australia. · Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, San Diego, United States. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom. · Signalling Programme, Babraham Institute, Cambridge, United Kingdom. · Francis Crick Institute, London, United Kingdom. · Therapeutics Research Centre, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia. ·Elife · Pubmed #29985127.

ABSTRACT: Intravital microscopy can provide unique insights into the function of biological processes in a native context. However, physiological motion caused by peristalsis, respiration and the heartbeat can present a significant challenge, particularly for functional readouts such as fluorescence lifetime imaging (FLIM), which require longer acquisition times to obtain a quantitative readout. Here, we present and benchmark

12 Article Intravital Imaging to Monitor Therapeutic Response in Moving Hypoxic Regions Resistant to PI3K Pathway Targeting in Pancreatic Cancer. 2018

Conway, James R W / Warren, Sean C / Herrmann, David / Murphy, Kendelle J / Cazet, Aurélie S / Vennin, Claire / Shearer, Robert F / Killen, Monica J / Magenau, Astrid / Mélénec, Pauline / Pinese, Mark / Nobis, Max / Zaratzian, Anaiis / Boulghourjian, Alice / Da Silva, Andrew M / Del Monte-Nieto, Gonzalo / Adam, Arne S A / Harvey, Richard P / Haigh, Jody J / Wang, Yingxiao / Croucher, David R / Sansom, Owen J / Pajic, Marina / Caldon, C Elizabeth / Morton, Jennifer P / Timpson, Paul. ·Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia. · Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia; Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia. · Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia; Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, NSW 2033, Australia. · Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia. · Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA. · Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland. · Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. · Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. Electronic address: j.morton@beatson.gla.ac.uk. · Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia. Electronic address: p.timpson@garvan.org.au. ·Cell Rep · Pubmed #29898401.

ABSTRACT: Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302.

13 Article MiR-142-3p is downregulated in aggressive p53 mutant mouse models of pancreatic ductal adenocarcinoma by hypermethylation of its locus. 2018

Godfrey, Jack D / Morton, Jennifer P / Wilczynska, Ania / Sansom, Owen J / Bushell, Martin D. ·Medical Research Council Toxicology Unit, Lancaster Rd, Leicester, LE1 7HB, UK. · Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK. · Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road Glasgow, Glasgow, G61 1QH, UK. · Medical Research Council Toxicology Unit, Lancaster Rd, Leicester, LE1 7HB, UK. mb446@le.ac.uk. ·Cell Death Dis · Pubmed #29844410.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognostic implications. This is partly due to a large proportion of PDACs carrying mutations in TP53, which impart gain-of-function characteristics that promote metastasis. There is evidence that microRNAs (miRNAs) may play a role in both gain-of-function TP53 mutations and metastasis, but this has not been fully explored in PDAC. Here we set out to identify miRNAs which are specifically dysregulated in metastatic PDAC. To achieve this, we utilised established mouse models of PDAC to profile miRNA expression in primary tumours expressing the metastasis-inducing mutant p53

14 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.

15 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.

16 Article Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G-Quadruplex-Binding Small Molecule. 2018

Marchetti, Chiara / Zyner, Katherine G / Ohnmacht, Stephan A / Robson, Mathew / Haider, Shozeb M / Morton, Jennifer P / Marsico, Giovanni / Vo, Tam / Laughlin-Toth, Sarah / Ahmed, Ahmed A / Di Vita, Gloria / Pazitna, Ingrida / Gunaratnam, Mekala / Besser, Rachael J / Andrade, Ana C G / Diocou, Seckou / Pike, Jeremy A / Tannahill, David / Pedley, R Barbara / Evans, T R Jeffry / Wilson, W David / Balasubramanian, Shankar / Neidle, Stephen. ·UCL School of Pharmacy , University College London , 29-39 Brunswick Square , London WC1N 1AX , U.K. · Cancer Research UK , Cambridge Research Institute , Li Ka Shing Centre, Robinson Way , Cambridge CB2 0RE , U.K. · Cancer Research UK Cancer Centre, UCL Cancer Institute , University College London , London WC1E 6BT , U.K. · Cancer Research UK , Beatson Institute , Garscube Estate, Switchback Road , Glasgow G61 1BD U.K. · Institute of Cancer Sciences . University of Glasgow , Glasgow G12 8QQ , U.K. · Department of Chemistry and Center for Biotechnology and Drug Design , Georgia State University , Atlanta , Georgia 30303-3083 , United States. · UCL Cancer Institute , University College London , London WC1E 6BT , U.K. · Department of Chemistry , University of Cambridge , Cambridge CB2 1EW , U.K. · The School of Clinical Medicine , University of Cambridge , Cambridge CB2 0SP , U.K. ·J Med Chem · Pubmed #29356532.

ABSTRACT: Human pancreatic ductal adenocarcinoma (PDAC) involves the dysregulation of multiple signaling pathways. A novel approach to the treatment of PDAC is described, involving the targeting of cancer genes in PDAC pathways having over-representation of G-quadruplexes, using the trisubstituted naphthalene diimide quadruplex-binding compound 2,7-bis(3-morpholinopropyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[ lmn][3,8]phenanthroline-1,3,6,8(2 H,7 H)-tetraone (CM03). This compound has been designed by computer modeling, is a potent inhibitor of cell growth in PDAC cell lines, and has anticancer activity in PDAC models, with a superior profile compared to gemcitabine, a commonly used therapy. Whole-transcriptome RNA-seq methodology has been used to analyze the effects of this quadruplex-binding small molecule on global gene expression. This has revealed the down-regulation of a large number of genes, rich in putative quadruplex elements and involved in essential pathways of PDAC survival, metastasis, and drug resistance. The changes produced by CM03 represent a global response to the complexity of human PDAC and may be applicable to other currently hard-to-treat cancers.

17 Article Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. 2018

Chou, Angela / Froio, Danielle / Nagrial, Adnan M / Parkin, Ashleigh / Murphy, Kendelle J / Chin, Venessa T / Wohl, Dalia / Steinmann, Angela / Stark, Rhys / Drury, Alison / Walters, Stacey N / Vennin, Claire / Burgess, Andrew / Pinese, Mark / Chantrill, Lorraine A / Cowley, Mark J / Molloy, Timothy J / Anonymous170925 / Waddell, Nicola / Johns, Amber / Grimmond, Sean M / Chang, David K / Biankin, Andrew V / Sansom, Owen J / Morton, Jennifer P / Grey, Shane T / Cox, Thomas R / Turchini, John / Samra, Jaswinder / Clarke, Stephen J / Timpson, Paul / Gill, Anthony J / Pajic, Marina. ·The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · Faculty of Medicine, St Vincent's Clinical School, University of NSW, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, SYDPATH, Darlinghurst, Australia. · Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. · St. Vincent's Hospital, Darlinghurst, Australia. · St Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales, Australia. · Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Queensland, Australia. · University of Melbourne, Melbourne, Victoria, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Department of Surgery, Cancer Research UK, Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, New South Wales, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia. ·Gut · Pubmed #29080858.

ABSTRACT: OBJECTIVE: Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. DESIGN: Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens). RESULTS: Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach. CONCLUSION: This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.

18 Article MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance. 2017

Farrell, Amy S / Joly, Meghan Morrison / Allen-Petersen, Brittany L / Worth, Patrick J / Lanciault, Christian / Sauer, David / Link, Jason / Pelz, Carl / Heiser, Laura M / Morton, Jennifer P / Muthalagu, Nathiya / Hoffman, Megan T / Manning, Sara L / Pratt, Erica D / Kendsersky, Nicholas D / Egbukichi, Nkolika / Amery, Taylor S / Thoma, Mary C / Jenny, Zina P / Rhim, Andrew D / Murphy, Daniel J / Sansom, Owen J / Crawford, Howard C / Sheppard, Brett C / Sears, Rosalie C. ·Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. · Department of Surgery, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. · Department of Pathology, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. · Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 S.W Sam Jackson Park Road, Portland, OR, 97239, USA. · Computational Biology, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. · Department of Biomedical Engineering and OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. · Cancer Research UK, Beatson Institute, Switchback Road, Bearsden, Glasgow, G61 1BD, UK. · Department of Molecular and Integrative Physiology, University of Michigan, 7744 MS II, 1137 E. Catherine St., Ann Arbor, MI, 48109, USA. · Department of Gastroenterology, Hepatology and Nutrition and Zayed Center for Pancreatic Cancer Research, University of Texas M.D. Anderson Cancer Center, Unit 1466, 1515 Holcombe Blvd, Houston, TX, 77030, USA. · Institute of Cancer Sciences, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK. · Knight Cancer Institute, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. · Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. searsr@ohsu.edu. · Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 S.W Sam Jackson Park Road, Portland, OR, 97239, USA. searsr@ohsu.edu. · Knight Cancer Institute, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. searsr@ohsu.edu. ·Nat Commun · Pubmed #29170413.

ABSTRACT: Intratumoral phenotypic heterogeneity has been described in many tumor types, where it can contribute to drug resistance and disease recurrence. We analyzed ductal and neuroendocrine markers in pancreatic ductal adenocarcinoma, revealing heterogeneous expression of the neuroendocrine marker Synaptophysin within ductal lesions. Higher percentages of Cytokeratin-Synaptophysin dual positive tumor cells correlate with shortened disease-free survival. We observe similar lineage marker heterogeneity in mouse models of pancreatic ductal adenocarcinoma, where lineage tracing indicates that Cytokeratin-Synaptophysin dual positive cells arise from the exocrine compartment. Mechanistically, MYC binding is enriched at neuroendocrine genes in mouse tumor cells and loss of MYC reduces ductal-neuroendocrine lineage heterogeneity, while deregulated MYC expression in KRAS mutant mice increases this phenotype. Neuroendocrine marker expression is associated with chemoresistance and reducing MYC levels decreases gemcitabine-induced neuroendocrine marker expression and increases chemosensitivity. Altogether, we demonstrate that MYC facilitates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma, contributing to poor survival and chemoresistance.

19 Article A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts. 2017

Nobis, Max / Herrmann, David / Warren, Sean C / Kadir, Shereen / Leung, Wilfred / Killen, Monica / Magenau, Astrid / Stevenson, David / Lucas, Morghan C / Reischmann, Nadine / Vennin, Claire / Conway, James R W / Boulghourjian, Alice / Zaratzian, Anaiis / Law, Andrew M / Gallego-Ortega, David / Ormandy, Christopher J / Walters, Stacey N / Grey, Shane T / Bailey, Jacqueline / Chtanova, Tatyana / Quinn, Julian M W / Baldock, Paul A / Croucher, Peter I / Schwarz, Juliane P / Mrowinska, Agata / Zhang, Lei / Herzog, Herbert / Masedunskas, Andrius / Hardeman, Edna C / Gunning, Peter W / Del Monte-Nieto, Gonzalo / Harvey, Richard P / Samuel, Michael S / Pajic, Marina / McGhee, Ewan J / Johnsson, Anna-Karin E / Sansom, Owen J / Welch, Heidi C E / Morton, Jennifer P / Strathdee, Douglas / Anderson, Kurt I / Timpson, Paul. ·The Garvan Institute of Medical Research, St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia. · Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G611BD, UK. · Neuromuscular and Regenerative Medicine Unit, University of New South Wales, Sydney, NSW 2010, Australia; Oncology Research Unit, School of Medical Sciences, University of New South Wales, Sydney, NSW 2010, Australia. · Neuromuscular and Regenerative Medicine Unit, University of New South Wales, Sydney, NSW 2010, Australia. · Oncology Research Unit, School of Medical Sciences, University of New South Wales, Sydney, NSW 2010, Australia. · Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; St. Vincent's Clinical School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia. · Centre for Cancer Biology, SA Pathology and University of South Australia School of Medicine, University of Adelaide, Adelaide, SA 5000, Australia. · Signalling Programme, Babraham Institute, Cambridge CB223AT, UK. · Francis Crick Institute, London NW11AT, UK. Electronic address: kurt.anderson@crick.ac.uk. · The Garvan Institute of Medical Research, 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 #28978480.

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.

20 Article Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. 2017

Vennin, Claire / Chin, Venessa T / Warren, Sean C / Lucas, Morghan C / Herrmann, David / Magenau, Astrid / Melenec, Pauline / Walters, Stacey N / Del Monte-Nieto, Gonzalo / Conway, James R W / Nobis, Max / Allam, Amr H / McCloy, Rachael A / Currey, Nicola / Pinese, Mark / Boulghourjian, Alice / Zaratzian, Anaiis / Adam, Arne A S / Heu, Celine / Nagrial, Adnan M / Chou, Angela / Steinmann, Angela / Drury, Alison / Froio, Danielle / Giry-Laterriere, Marc / Harris, Nathanial L E / Phan, Tri / Jain, Rohit / Weninger, Wolfgang / McGhee, Ewan J / Whan, Renee / Johns, Amber L / Samra, Jaswinder S / Chantrill, Lorraine / Gill, Anthony J / Kohonen-Corish, Maija / Harvey, Richard P / Biankin, Andrew V / Anonymous3070902 / Evans, T R Jeffry / Anderson, Kurt I / Grey, Shane T / Ormandy, Christopher J / Gallego-Ortega, David / Wang, Yingxiao / Samuel, Michael S / Sansom, Owen J / Burgess, Andrew / Cox, Thomas R / Morton, Jennifer P / Pajic, Marina / Timpson, Paul. ·The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. · St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia. · Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia. · Biomedical Imaging Facility, Mark Wainwright Analytical Centre, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia. · Department of Pathology, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia. · Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales 2522, Australia. · Immune Imaging Program, Centenary Institute, University of Sydney, Sydney, New South Wales 2006, Australia. · University of Sydney Medical School, Sydney, New South Wales 2006, Australia. · Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. · Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K. · Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research and Royal North Shore Hospital, Sydney, New South Wales 2065, Australia. · University of Sydney, Sydney, New South Wales 2006, Australia. · Australian Pancreatic Cancer Genome Initiative. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia. · Macarthur Cancer Therapy Centre, Campbelltown Hospital, Sydney, New South Wales 2560, Australia. · School of Medicine, Western Sydney University, Penrith, Sydney, New South Wales 2751, Australia. · School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, New South Wales 2052, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Scotland G61 BD, U.K. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Scotland G61 BD, U.K. · Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, San Diego, CA 92121, USA. · Centre for Cancer Biology, SA Pathology and University of South Australia School of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia. · The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. m.pajic@garvan.org.au p.timpson@garvan.org.au. ·Sci Transl Med · Pubmed #28381539.

ABSTRACT: The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.

21 Article SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer. 2017

Harris, N L E / Vennin, C / Conway, J R W / Vine, K L / Pinese, M / Cowley, M J / Shearer, R F / Lucas, M C / Herrmann, D / Allam, A H / Pajic, M / Morton, J P / Anonymous2000901 / Biankin, A V / Ranson, M / Timpson, P / Saunders, D N. ·Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia. · Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, Australia. · School of Biological Sciences, University of Wollongong, Wollongong, Australia. · Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, Australia. · Cancer Research UK Beatson Institute, Glasgow, Scotland. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · School of Medical Sciences, University of New South Wales, Sydney, Australia. ·Oncogene · Pubmed #28346421.

ABSTRACT: Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2

22 Article Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion. 2017

Gundry, Christine / Marco, Sergi / Rainero, Elena / Miller, Bryan / Dornier, Emmanuel / Mitchell, Louise / Caswell, Patrick T / Campbell, Andrew D / Hogeweg, Anna / Sansom, Owen J / Morton, Jennifer P / Norman, Jim C. ·CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK. · Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. · Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK. ·Nat Commun · Pubmed #28294115.

ABSTRACT: The Rab GTPase effector, Rab-coupling protein (RCP) is known to promote invasive behaviour in vitro by controlling integrin and receptor tyrosine kinase (RTK) trafficking, but how RCP influences metastasis in vivo is unclear. Here we identify an RTK of the Eph family, EphA2, to be a cargo of an RCP-regulated endocytic pathway which controls cell:cell repulsion and metastasis in vivo. Phosphorylation of RCP at Ser

23 Article ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth. 2017

Rath, Nicola / Morton, Jennifer P / Julian, Linda / Helbig, Lena / Kadir, Shereen / McGhee, Ewan J / Anderson, Kurt I / Kalna, Gabriela / Mullin, Margaret / Pinho, Andreia V / Rooman, Ilse / Samuel, Michael S / Olson, Michael F. ·Cancer Research UK Beatson Institute, Glasgow, UK. · Electron Microscopy Facility, School of Life Sciences, University of Glasgow, Glasgow, UK. · Cancer Research Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia. · Oncology Research Centre, Free University Brussels (VUB), Brussels, Belgium. · Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, Australia. · Cancer Research UK Beatson Institute, Glasgow, UK m.olson@beatson.gla.ac.uk. · Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. ·EMBO Mol Med · Pubmed #28031255.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death; identifying PDAC enablers may reveal potential therapeutic targets. Expression of the actomyosin regulatory ROCK1 and ROCK2 kinases increased with tumor progression in human and mouse pancreatic tumors, while elevated ROCK1/ROCK2 expression in human patients, or conditional ROCK2 activation in a Kras

24 Article Hypermutation In Pancreatic Cancer. 2017

Humphris, Jeremy L / Patch, Ann-Marie / Nones, Katia / Bailey, Peter J / Johns, Amber L / McKay, Skye / Chang, David K / Miller, David K / Pajic, Marina / Kassahn, Karin S / Quinn, Michael C J / Bruxner, Timothy J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Stone, Andrew / Wilson, Peter J / Anderson, Matthew / Fink, J Lynn / Holmes, Oliver / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Mead, Ronald S / Xu, Qinying / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Nagrial, Adnan M / Chin, Venessa T / Chantrill, Lorraine A / Mawson, Amanda / Chou, Angela / Scarlett, Christopher J / Pinho, Andreia V / Rooman, Ilse / Giry-Laterriere, Marc / Samra, Jaswinder S / Kench, James G / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Jamieson, Nigel B / McKay, Colin J / Carter, C Ross / Dickson, Euan J / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Morton, Jennifer P / Sansom, Owen J / Grützmann, Robert / Hruban, Ralph H / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Schulick, Richard D / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Rusev, Borislav / Corbo, Vincenzo / Salvia, Roberto / Cataldo, Ivana / Tortora, Giampaolo / Tempero, Margaret A / Anonymous5070887 / Hofmann, Oliver / Eshleman, James R / Pilarsky, Christian / Scarpa, Aldo / Musgrove, Elizabeth A / Gill, Anthony J / Pearson, John V / Grimmond, Sean M / Waddell, Nicola / Biankin, Andrew V. ·The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Genetic and Molecular Pathology, Adelaide, South Australia, Australia; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; South Eastern Area Laboratory Services Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia; Sonic Genetics, Douglass Hanly Moir Pathology, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Department of Anatomical Pathology, SydPath, St Vincent's Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. · Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; School of Medicine, Western Sydney University, Penrith, New South Wales, Australia. · Department of Surgery, Fiona Stanley Hospital, Murdoch, Washington. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia. · Department of Surgery, Princess Alexandra Hospital, Woollongabba, Queensland, Australia. · School of Surgery, University of Western Australia, Australia and St John of God Pathology, Subiaco, Washington. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. · Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde National Health Service, Glasgow, United Kingdom. · Greater Glasgow and Clyde Bio-repository, Pathology Department, Queen Elizabeth University Hospital, Glasgow, United Kingdom. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute for Cancer Science, University of Glasgow, Glasgow, United Kingdom. · Universitätsklinikum Erlangen, Erlangen, Germany. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Medicine, University and Hospital Trust of Verona, Verona, Italy. · Division of Hematology and Oncology, University of California, San Francisco, California. · Australian Pancreatic Cancer Genome Initiative. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Universitätsklinikum Erlangen, Department of Surgery, University of Erlangen-Nueremberg, Germany. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. Electronic address: nic.waddell@qimrberghofer.edu.au. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. Electronic address: andrew.biankin@glasgow.ac.uk. ·Gastroenterology · Pubmed #27856273.

ABSTRACT: Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

25 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.

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