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Pancreatic Neoplasms: HELP
Articles by Andrew D. Rhim
Based on 32 articles published since 2009
(Why 32 articles?)
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Between 2009 and 2019, Andrew Rhim wrote the following 32 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial A New Scalpel for the Treatment of Pancreatic Cancer: Targeting Stromal-Derived STAT3 Signaling. 2015

Cowan, Robert W / Maitra, Anirban / Rhim, Andrew D. ·Division of Gastroenterology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan. · Departments of Pathology and Translational Molecular Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas. · Division of Gastroenterology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan. Electronic address: arhim@med.umich.edu. ·Gastroenterology · Pubmed #26526714.

ABSTRACT: -- No abstract --

2 Review Can Stopping Nerves, Stop Cancer? 2016

Saloman, Jami L / Albers, Kathryn M / Rhim, Andrew D / Davis, Brian M. ·University of Pittsburgh, Center for Pain Research and Department of Neurobiology, Pittsburgh, PA 15261, USA. Electronic address: jls354@pitt.edu. · University of Pittsburgh, Center for Pain Research and Department of Neurobiology, Pittsburgh, PA 15261, USA. · Zayed Center for Pancreatic Cancer Research and Department of Gastroenterology, Hepatology and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. ·Trends Neurosci · Pubmed #27832915.

ABSTRACT: The nervous system is viewed as a tissue affected by cancer and as a conduit for the transmission of cancer pain and perineural invasion. Here, we review recent studies that indicate a more direct role. Several studies have shown that reducing stress or suppressing sympathetic drive correlates with improved outcomes and prolonged survival. Recent studies using animal models of visceral and somatic cancer further support a role for the nervous system in cancer progression. Specifically, nerve ablation had a profound impact on disease progression, including delayed development of precancerous lesions, and decreased tumor growth and metastasis. In this review, we summarize new evidence and discuss how future studies may address the role of neural signaling in the modulation of tumorigenesis.

3 Review Early detection of sporadic pancreatic cancer: summative review. 2015

Chari, Suresh T / Kelly, Kimberly / Hollingsworth, Michael A / Thayer, Sarah P / Ahlquist, David A / Andersen, Dana K / Batra, Surinder K / Brentnall, Teresa A / Canto, Marcia / Cleeter, Deborah F / Firpo, Matthew A / Gambhir, Sanjiv Sam / Go, Vay Liang W / Hines, O Joe / Kenner, Barbara J / Klimstra, David S / Lerch, Markus M / Levy, Michael J / Maitra, Anirban / Mulvihill, Sean J / Petersen, Gloria M / Rhim, Andrew D / Simeone, Diane M / Srivastava, Sudhir / Tanaka, Masao / Vinik, Aaron I / Wong, David. ·From the *Department of Medicine, Mayo Clinic, Rochester, MN; †Department of Biomedical Engineering, University of Virginia, Charlottesville, VA; Departments of ‡Biochemistry and Molecular Biology, §Pathology and Microbiology, and ∥Surgery, Fred & Pamela Buffett Cancer Center, University of Nebraska, Omaha, NE; ¶Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD; #Division of Gastroenterology, University of Washington, Seattle, WA; **Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD; ††Sawgrass Leadership Institute, Ponte Vedra Beach, FL; ‡‡Department of Surgery, University of Utah, Salt Lake City, UT; §§Department of Radiology, Stanford University School of Medicine, Stanford; ∥∥Department of Medicine, David Geffen School of Medicine, and ¶¶General Surgery, University of California Los Angeles, Los Angeles, CA; ##Kenner Family Research Fund; ***Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY; †††Department of Internal Medicine, University of Greifswald, Greifswald, Germany; ‡‡‡Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX; §§§Department of Health Sciences Research, Mayo Clinic, Rochester, MN; ∥∥∥Gastroenterology Division, Department of Internal Medicine and Comprehensive Cancer Center, and ¶¶¶Department of Surgery, School of Medicine, University of Michigan, Ann Arbor, MI; ###Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD; ****Departments of Surgery and Oncology, Kyushu University, Fukuoka, Japan; ††††Department of Medicine, Eastern Virginia Medical School, Norfolk, VA; and ‡‡‡‡Division of Oral Biology and Medicine, CLA School of Dentistry, Jonnson Comprehensive Cancer Center, University of California Los Angeles, L ·Pancreas · Pubmed #25931254.

ABSTRACT: Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC.

4 Review Molecular biology of pancreatic ductal adenocarcinoma. 2014

Coleman, Stacey J / Rhim, Andrew D. ·aDivision of Gastroenterology, Department of Internal Medicine bComprehensive Cancer Center, University of Michigan Medical School, Michigan, USA. ·Curr Opin Gastroenterol · Pubmed #25023382.

ABSTRACT: PURPOSE OF REVIEW: Recent advances in sequencing technology have led to a deeper and more comprehensive understanding of the molecular biology of pancreatic ductal adenocarcinoma. This timely review seeks to summarize these recent advances which will provide a foundation for future studies in the field. RECENT FINDINGS: Stereotypical genetic alterations have been identified and confirmed. However, additional alterations have highlighted the importance and complexity of a number of intracellular signaling pathways that present unique opportunities for therapeutic targeting. SUMMARY: A genetic signature of pancreatic ductal adenocarcinoma has been identified. This recent and important work is currently in the process of being applied in many clinical applications from early diagnostics to customized therapeutic regimens for this disease. A fundamental understanding of these findings will thus be of utmost importance for future research in the field and in the clinical care of patients with this lethal disease.

5 Review Epithelial to mesenchymal transition and the generation of stem-like cells in pancreatic cancer. 2013

Rhim, Andrew D. ·Gastroenterology Division and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. arhim@mail.med.upenn.edu ·Pancreatology · Pubmed #23561968.

ABSTRACT: An epithelial-to-mesenchymal transition (EMT) is thought to be an important process in the acquisition of capabilities required for metastasis. Until recently, studies of EMT involved mostly in vitro assays and transplantation experiments of cancer cells that overexpressed known EMT drivers. While valuable, these studies do not allow us to conclude if an EMT sustained under "physiologic conditions" within the tumor microenvironment leads to the myriad changes in phenotype observed in vitro. Here we review our recently published work using a lineage labeled genetically engineered mouse model of pancreatic ductal adenocarcinoma to characterize cells that have sustained an EMT in vivo.

6 Review Molecular biology of pancreatic ductal adenocarcinoma progression: aberrant activation of developmental pathways. 2010

Rhim, Andrew D / Stanger, Ben Z. ·Gastroenterology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. ·Prog Mol Biol Transl Sci · Pubmed #21074729.

ABSTRACT: Embryonic development marks a period of peak tissue growth and morphogenesis in the mammalian lifecycle. Many of the pathways that underlie cell proliferation and movement are relatively quiescent in adult animals but become reactivated during carcinogenesis. This phenomenon has been particularly well documented in pancreatic cancer, where detailed genetic studies and a robust mouse model have permitted investigators to test the role of various developmental signals in cancer progression. In this chapter, we review current knowledge regarding the signaling pathways that act during pancreatic development and the evidence that the reactivation of developmentally important signals is critical for the pathogenesis of this treatment-refractory malignancy.

7 Article ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis. 2019

Wang, Lidong / Yang, Huibin / Zamperone, Andrea / Diolaiti, Daniel / Palmbos, Phillip L / Abel, Ethan V / Purohit, Vinee / Dolgalev, Igor / Rhim, Andrew D / Ljungman, Mats / Hadju, Christina H / Halbrook, Christopher J / Bar-Sagi, Dafna / di Magliano, Marina Pasca / Crawford, Howard C / Simeone, Diane M. ·Department of Surgery, New York University School of Medicine, New York, New York 10016, USA. · Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, New York 10016, USA. · Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. · Department of Pathology, New York University School of Medicine, New York, New York 10016, USA. · Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA. · Department of Medicine, New York University School of Medicine, New York, New York 10016, USA. · Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. ·Genes Dev · Pubmed #31048544.

ABSTRACT: Pancreatic adenocarcinoma (PDA) is an aggressive disease driven by oncogenic KRAS and characterized by late diagnosis and therapeutic resistance. Here we show that deletion of the ataxia-telangiectasia group D-complementing (

8 Article Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer. 2018

Reichert, Maximilian / Bakir, Basil / Moreira, Leticia / Pitarresi, Jason R / Feldmann, Karin / Simon, Lauren / Suzuki, Kensuke / Maddipati, Ravikanth / Rhim, Andrew D / Schlitter, Anna M / Kriegsmann, Mark / Weichert, Wilko / Wirth, Matthias / Schuck, Kathleen / Schneider, Günter / Saur, Dieter / Reynolds, Albert B / Klein-Szanto, Andres J / Pehlivanoglu, Burcin / Memis, Bahar / Adsay, N Volkan / Rustgi, Anil K. ·Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University Munich, Medizinische Klinik, Ismaninger Str. 22, Munich 81675, Germany. Electronic address: maximilian.reichert@tum.de. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), IDIBAPS, University of Barcelona, Catalonia, Spain. · Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University Munich, Medizinische Klinik, Ismaninger Str. 22, Munich 81675, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. · Division of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center, Houston, TX, USA. · Institute of General Pathology and Pathological Anatomy, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. · Institute of Pathology, Heidelberg University, Heidelberg, Germany. · Institute of Pathology, Heinrich-Heine University and University Hospital Düsseldorf, Düsseldorf 40225, Germany. · Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA. · Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA, USA. · Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA, USA. · Department of Pathology, Koc University Hospital, Istanbul, Turkey. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA. Electronic address: anil2@pennmedicine.upenn.edu. ·Dev Cell · Pubmed #29920275.

ABSTRACT: The regulation of metastatic organotropism in pancreatic ductal a denocarcinoma (PDAC) remains poorly understood. We demonstrate, using multiple mouse models, that liver and lung metastatic organotropism is dependent upon p120catenin (p120ctn)-mediated epithelial identity. Mono-allelic p120ctn loss accelerates Kras

9 Article Loss of Pten and Activation of Kras Synergistically Induce Formation of Intraductal Papillary Mucinous Neoplasia From Pancreatic Ductal Cells in Mice. 2018

Kopp, Janel L / Dubois, Claire L / Schaeffer, David F / Samani, Atefeh / Taghizadeh, Farnaz / Cowan, Robert W / Rhim, Andrew D / Stiles, Bangyan L / Valasek, Mark / Sander, Maike. ·Departments of Pediatrics and Cellular and Molecular Medicine, University of California-San Diego, La Jolla, California; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada. · Departments of Pediatrics and Cellular and Molecular Medicine, University of California-San Diego, La Jolla, California. · Department of Pathology and Laboratory and Medicine, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada. · Ahmed Center for Pancreatic Cancer Research and Department of Gastroenterology, Hepatology and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston, Texas. · Department of Pharmaceutical Sciences, School of Pharmacy, Keck School of Medicine, University of Southern California, and the Norris Comprehensive Cancer Center, Los Angeles, California. · Department of Pathology, University of California-San Diego, La Jolla, California. · Departments of Pediatrics and Cellular and Molecular Medicine, University of California-San Diego, La Jolla, California. Electronic address: masander@ucsd.edu. ·Gastroenterology · Pubmed #29273451.

ABSTRACT: BACKGROUND & AIMS: Intraductal papillary mucinous neoplasias (IPMNs) are precancerous cystic lesions that can develop into pancreatic ductal adenocarcinomas (PDACs). These large macroscopic lesions are frequently detected during medical imaging, but it is unclear how they form or progress to PDAC. We aimed to identify cells that form IPMNs and mutations that promote IPMN development and progression. METHODS: We generated mice with disruption of Pten specifically in ductal cells (Sox9CreER RESULTS: Mice with ductal cell-specific disruption of Pten but not control mice developed sporadic, macroscopic, intraductal papillary lesions with histologic and molecular features of human IPMNs. Pten CONCLUSIONS: In analyses of mice with ductal cell-specific disruption of Pten, with or without activated Kras, we found evidence for a ductal cell origin of IPMNs. We also showed that PTEN loss and activated Kras have synergistic effects in promoting development of IPMN and progression to PDAC.

10 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.

11 Article 3rd St. Gallen EORTC Gastrointestinal Cancer Conference: Consensus recommendations on controversial issues in the primary treatment of pancreatic cancer. 2017

Lutz, Manfred P / Zalcberg, John R / Ducreux, Michel / Aust, Daniela / Bruno, Marco J / Büchler, Markus W / Delpero, Jean-Robert / Gloor, Beat / Glynne-Jones, Rob / Hartwig, Werner / Huguet, Florence / Laurent-Puig, Pierre / Lordick, Florian / Maisonneuve, Patrick / Mayerle, Julia / Martignoni, Marc / Neoptolemos, John / Rhim, Andrew D / Schmied, Bruno M / Seufferlein, Thomas / Werner, Jens / van Laethem, Jean-Luc / Otto, Florian. ·CaritasKlinikum St. Theresia, Saarbrücken, Germany. Electronic address: m.lutz@caritasklinikum.de. · Department of Epidemiology and Preventive Medicine, School of Public Health, Monash University, The Alfred Centre, Melbourne, Australia. · Institut Gustave Roussy, Villejuif, France. · Department of Pathology, Universitätsklinikum Carl Gustav Carus, Dresden, Germany. · Department of Gastroenterology & Hepatology, Erasmus Medical Center, University Medical Center Rotterdam, The Netherlands. · Chirurgische Universitätsklinik, Heidelberg, Germany. · Department of Surgery, Institut Paoli Calmettes, Marseille, France. · Klinik für Viszerale und Transplantationschirurgie, Inselspital, Bern, Switzerland. · Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK. · Department of General, Visceral and Transplantation Surgery, Klinikum der Universität München, Munich, Germany. · Radiooncology Service, Hôpital Tenon (Hôpitaux Universitaires Est Parisien), Paris Cedex 20, France. · Université René Descartes, UFR Biomédicale des Saints-Pères, Paris, France. · University Cancer Center Leipzig (UCCL), University Medicine Leipzig, Germany. · Istituto Europeo di Oncologia, Divisione di Epidemiologia e Biostatistica, Milan, Italy. · Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin, Greifswald, Germany; Medizinische Klinik und Poliklinik II, Klinikum der Universität München, Munich, Germany. · Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, TU München, Munich, Germany. · Department of Surgery, Liverpool University, Liverpool, UK. · University of Michigan, Ann Arbor, MI, USA. · Klinik für Chirurgie, Kantonsspital St. Gallen, St. Gallen, Switzerland. · Department of Internal Medicine I, Ulm University, Ulm, Germany. · Hopital Erasme, Anderlecht, Belgium. · Tumor- und Brustzentrum ZeTuP, St. Gallen, Switzerland. ·Eur J Cancer · Pubmed #28460245.

ABSTRACT: The primary treatment of pancreatic cancer was the topic of the 3rd St. Gallen Conference 2016. A multidisciplinary panel reviewed the current evidence and discussed controversial issues in a moderated consensus session. Here we report on the key expert recommendations. It was generally accepted that radical surgical resection followed by adjuvant chemotherapy offers the only evidence-based treatment with a chance for cure. Initial staging should classify localised tumours as resectable or unresectable (i.e. locally advanced pancreatic cancer) although there remains a large grey-zone of potentially resectable disease between these two categories which has recently been named as borderline resectable, a concept which was generally accepted by the panel members. However, the definition of these borderline-resectable (BR) tumours varies between classifications due to their focus on either (i) technical hurdles (e.g. the feasibility of vascular resection) or (ii) oncological outcome (e.g. predicting the risk of a R1 resection and/or occult metastases). The resulting expert discussion focussed on imaging standards as well as the value of pretherapeutic laparoscopy. Indications for biliary drainage were seen especially before neoadjuvant therapy. Following standard resection, the panel unanimously voted for the use of adjuvant chemotherapy after R0 resection and considered it as a reasonable standard of care after R1 resection, even though the optimal pathologic evaluation and the definition of R0/R1 was the issue of an ongoing debate. The general concept of BR tumours was considered as a good basis to select patients for preoperative therapy, albeit its current impact on the therapeutic strategy was far less clear. Main focus of the conference was to discuss the limits of surgical resection and to identify ways to standardise procedures and to improve curative outcome, including adjuvant and perioperative treatment.

12 Article A Clinical Prediction Model to Assess Risk for Pancreatic Cancer Among Patients With New-Onset Diabetes. 2017

Boursi, Ben / Finkelman, Brian / Giantonio, Bruce J / Haynes, Kevin / Rustgi, Anil K / Rhim, Andrew D / Mamtani, Ronac / Yang, Yu-Xiao. ·Department of Medicine and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Tel-Aviv University, Tel-Aviv, Israel. · Department of Medicine and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Medicine and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. · Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research and Department of Gastroenterology, Hepatology and Nutrition, University of Texas, MD Anderson Cancer Center, Houston, Texas. · Department of Medicine and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: yangy@mail.med.upenn.edu. ·Gastroenterology · Pubmed #27923728.

ABSTRACT: BACKGROUND & AIMS: Approximately 50% of all patients with pancreatic ductal adenocarcinoma (PDA) develop diabetes mellitus before their cancer diagnosis. Screening individuals with new-onset diabetes might allow earlier diagnosis of PDA. We sought to develop and validate a PDA risk prediction model to identify high-risk individuals among those with new-onset diabetes. METHODS: We conducted a retrospective cohort study in a population representative database from the United Kingdom. Individuals with incident diabetes after the age of 35 years and 3 or more years of follow-up after diagnosis of diabetes were eligible for inclusion. Candidate predictors consisted of epidemiologic and clinical characteristics available at the time of diabetes diagnosis. Variables with P values <.25 in the univariable analyses were evaluated using backward stepwise approach. Model discrimination was assessed using receiver operating characteristic curve analysis. Calibration was evaluated using the Hosmer-Lemeshow test. Results were internally validated using a bootstrapping procedure. RESULTS: We analyzed data from 109,385 patients with new-onset diabetes. Among them, 390 (0.4%) were diagnosed with PDA within 3 years. The final model (area under the curve, 0.82; 95% confidence interval, 0.75-0.89) included age, body mass index, change in body mass index, smoking, use of proton pump inhibitors, and anti-diabetic medications, as well as levels of hemoglobin A1C, cholesterol, hemoglobin, creatinine, and alkaline phosphatase. Bootstrapping validation showed negligible optimism. If the predicted risk threshold for definitive PDA screening was set at 1% over 3 years, only 6.19% of the new-onset diabetes population would undergo definitive screening, which would identify patients with PDA with 44.7% sensitivity, 94.0% specificity, and a positive predictive value of 2.6%. CONCLUSIONS: We developed a risk model based on widely available clinical parameters to help identify patients with new-onset diabetes who might benefit from PDA screening.

13 Article Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer. 2017

Zhang, Yaqing / Velez-Delgado, Ashley / Mathew, Esha / Li, Dongjun / Mendez, Flor M / Flannagan, Kevin / Rhim, Andrew D / Simeone, Diane M / Beatty, Gregory L / Pasca di Magliano, Marina. ·Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA. · Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA. · Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA. · Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA. · Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA. · Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, Philadelphia, Pennsylvania, USA. · Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA. ·Gut · Pubmed #27402485.

ABSTRACT: BACKGROUND: Pancreatic cancer is characterised by the accumulation of a fibro-inflammatory stroma. Within this stromal reaction, myeloid cells are a predominant population. Distinct myeloid subsets have been correlated with tumour promotion and unmasking of anti-tumour immunity. OBJECTIVE: The goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer and to understand the relationship between myeloid cells and T cell-mediated immunity within the pancreatic cancer microenvironment. METHODS: Primary mouse pancreatic cancer cells were transplanted into CD11b-diphtheria toxin receptor (DTR) mice. Alternatively, the iKras* mouse model of pancreatic cancer was crossed into CD11b-DTR mice. CD11b RESULTS: Depletion of myeloid cells prevented Kras CONCLUSION: Our results show that myeloid cells support immune evasion in pancreatic cancer through EGFR/MAPK-dependent regulation of PD-L1 expression on tumour cells. Derailing this crosstalk between myeloid cells and tumour cells is sufficient to restore anti-tumour immunity mediated by CD8

14 Article Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. 2016

Saloman, Jami L / Albers, Kathryn M / Li, Dongjun / Hartman, Douglas J / Crawford, Howard C / Muha, Emily A / Rhim, Andrew D / Davis, Brian M. ·Center for Pain Research and Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261; · Comprehensive Cancer Center and Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109; · Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261; · Department of Internal Medicine, Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109. · Comprehensive Cancer Center and Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109; bmd1@pitt.edu arhim@med.umich.edu. · Center for Pain Research and Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261; bmd1@pitt.edu arhim@med.umich.edu. ·Proc Natl Acad Sci U S A · Pubmed #26929329.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

15 Article Orthotopic Injection of Pancreatic Cancer Cells. 2016

Aiello, Nicole M / Rhim, Andrew D / Stanger, Ben Z. ·Department of Gastroenterology and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104. ·Cold Spring Harb Protoc · Pubmed #26729902.

ABSTRACT: Pancreatic ductal adenocarcinoma is an aggressive disease with a 5-yr survival rate of only 5%. The location of the pancreas in the abdomen, where it is obscured by other organs, makes it a difficult tissue to study and manipulate. This protocol describes in detail how to orthotopically inject cancer cells into the pancreas in mice. This technique is particularly useful when the cells must be manipulated in ways that cannot be modeled genetically.

16 Article Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer. 2016

Roberts, Nicholas J / Norris, Alexis L / Petersen, Gloria M / Bondy, Melissa L / Brand, Randall / Gallinger, Steven / Kurtz, Robert C / Olson, Sara H / Rustgi, Anil K / Schwartz, Ann G / Stoffel, Elena / Syngal, Sapna / Zogopoulos, George / Ali, Syed Z / Axilbund, Jennifer / Chaffee, Kari G / Chen, Yun-Ching / Cote, Michele L / Childs, Erica J / Douville, Christopher / Goes, Fernando S / Herman, Joseph M / Iacobuzio-Donahue, Christine / Kramer, Melissa / Makohon-Moore, Alvin / McCombie, Richard W / McMahon, K Wyatt / Niknafs, Noushin / Parla, Jennifer / Pirooznia, Mehdi / Potash, James B / Rhim, Andrew D / Smith, Alyssa L / Wang, Yuxuan / Wolfgang, Christopher L / Wood, Laura D / Zandi, Peter P / Goggins, Michael / Karchin, Rachel / Eshleman, James R / Papadopoulos, Nickolas / Kinzler, Kenneth W / Vogelstein, Bert / Hruban, Ralph H / Klein, Alison P. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. · Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. · Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. · Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. · Population Sciences Division, Dana-Farber Cancer Institute, and Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts. · The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. · Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland. · Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Memorial Sloan Kettering Cancer Center, New York, New York. · Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. inGenious Targeting Laboratory, Ronkonkoma, New York. · Department of Psychiatry, University of Iowa, Iowa City, Iowa. · Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Medicine, University of Michigan, Ann Arbor, Michigan. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu. ·Cancer Discov · Pubmed #26658419.

ABSTRACT: SIGNIFICANCE: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer.

17 Article Creation of primary cell lines from lineage-labeled mouse models of cancer. 2015

Rhim, Andrew D. ·Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109. ·Cold Spring Harb Protoc · Pubmed #25934932.

ABSTRACT: Frequently, it is necessary to isolate pure populations of cancer cells for downstream assays, such as transcriptional analysis, signaling studies, and the creation of noncontaminated primary cell lines. Genetic lineage labeling with fluorescent reporter alleles allows for the identification of epithelial-derived cells within tumors. This protocol describes a method to isolate lineage-labeled pancreatic epithelial cells for ex vivo analysis, but it can be adapted for any type of lineage-labeled tumor.

18 Article Doublecortin-like kinase 1 is elevated serologically in pancreatic ductal adenocarcinoma and widely expressed on circulating tumor cells. 2015

Qu, Dongfeng / Johnson, Jeremy / Chandrakesan, Parthasarathy / Weygant, Nathaniel / May, Randal / Aiello, Nicole / Rhim, Andrew / Zhao, Lichao / Zheng, Wei / Lightfoot, Stanley / Pant, Shubham / Irvan, Jeremy / Postier, Russell / Hocker, James / Hanas, Jay S / Ali, Naushad / Sureban, Sripathi M / An, Guangyu / Schlosser, Michael J / Stanger, Ben / Houchen, Courtney W. ·Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Department of Veterans Affairs Medical Center, Oklahoma City, OK, United States of America; Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK, United States of America. · Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America. · Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK, United States of America. · Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America. · Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Department of Veterans Affairs Medical Center, Oklahoma City, OK, United States of America. · Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America. · Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States of America. · Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America. · Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America. · Department of Oncology, Beijing Chaoyang Hospital, Capital Medicinal University, Beijing, China. · COARE Biotechnology Inc., Oklahoma City, OK, United States of America. · Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Department of Veterans Affairs Medical Center, Oklahoma City, OK, United States of America; Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK, United States of America; COARE Biotechnology Inc., Oklahoma City, OK, United States of America. ·PLoS One · Pubmed #25723399.

ABSTRACT: Doublecortin-like kinase 1 (DCLK1) is a putative pancreatic stem cell marker and is upregulated in pancreatic cancer, colorectal cancer, and many other solid tumors. It marks tumor stem cells in mouse models of intestinal neoplasia. Here we sought to determine whether DCLK1 protein can be detected in the bloodstream and if its levels in archived serum samples could be quantitatively assessed in pancreatic cancer patients. DCLK1 specific ELISA, western blotting, and immunohistochemical analyses were used to determine expression levels in the serum and staining intensity in archived tumor tissues of pancreatic ductal adenocarcinoma (PDAC) patients and in pancreatic cancer mouse models. DCLK1 levels in the serum were elevated in early stages of PDAC (stages I and II) compared to healthy volunteers (normal controls). No differences were observed between stages III/IV and normal controls. In resected surgical tissues, DCLK1 expression intensity in the stromal cells was significantly higher than that observed in tumor epithelial cells. Circulating tumor cells were isolated from KPCY mice and approximately 52% of these cells were positive for Dclk1 staining. Dclk1 levels in the serum of KPC mice were also elevated. We have previously demonstrated that DCLK1 plays a potential role in regulating epithelial mesenchymal transition (EMT). Given the increasingly recognized role of EMT derived stem cells in cancer progression and metastasis, we hypothesize that DCLK1 may contribute to the metastatic process. Taken together, our results suggest that DCLK1 serum levels and DCLK1 positive circulating tumor cells should be further assessed for their potential diagnostic and prognostic significance.

19 Article ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis. 2015

Wang, Lidong / Yang, Huibin / Abel, Ethan V / Ney, Gina M / Palmbos, Phillip L / Bednar, Filip / Zhang, Yaqing / Leflein, Jacob / Waghray, Meghna / Owens, Scott / Wilkinson, John E / Prasad, Jayendra / Ljungman, Mats / Rhim, Andrew D / Pasca di Magliano, Marina / Simeone, Diane M. ·Department of Surgery, Translational Oncology Program. · Translational Oncology Program, Department of Pediatrics. · Translational Oncology Program, Department of Internal Medicine. · Department of Surgery. · Department of Pathology. · Department of Laboratory Animal Medicine. · Translational Oncology Program, Department of Radiation Oncology, Department of Molecular and Integrative Physiology. · Department of Internal Medicine. · Department of Surgery, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Surgery, Translational Oncology Program, Department of Molecular and Integrative Physiology, simeone@med.umich.edu. ·Genes Dev · Pubmed #25593307.

ABSTRACT: The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of β-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.

20 Article Polarization of the vacuolar adenosine triphosphatase delineates a transition to high-grade pancreatic intraepithelial neoplasm lesions. 2014

Sreekumar, Bharath K / Belinsky, Glenn S / Einwachter, Henrik / Rhim, Andrew D / Schmid, Roland / Chung, Chuhan. ·From the *Department of Medicine, Yale University School of Medicine, New Haven, CT; †Second Department of Internal Medicine, Klinikum rechts der Isar, Technical University, Munich, Germany; ‡Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI; and §Veterans Administration CT Healthcare System, West Haven, CT. ·Pancreas · Pubmed #25072283.

ABSTRACT: OBJECTIVES: A functional vacuolar adenosine triphosphatase (v-ATPase) complex regulates canonical Wnt/β-catenin signaling. The goal of this study was to identify the distribution of the v-ATPase in human and murine models of pancreatic intraepithelial neoplasms (PanINs) and assess its role in Wnt/β-catenin signaling. METHODS: We evaluated the immunolabeling pattern of the v-ATPase in human PanIN specimens and murine PanIN-1 and PanIN-2 lesions obtained from Ptf1a(Cre/+); LSL-Kras(G12D) mice. Wnt/β-catenin signaling was interrogated in primary PanIN cells by examining the phosphorylated levels of its surface coreceptor, low-density lipoprotein receptor-related protein-6 (LRP6), and its intracellular effector, nonphosphorylated β-catenin. The response of primary PanIN cells to epidermal growth factor (EGF) was assessed in the absence and presence of the v-ATPase inhibitor, concanamycin. RESULTS: In advanced (PanIN-2), but not early (PanIN-1), lesions, the v-ATPase assumed a polarized phenotype. Blocking the v-ATPase disrupted Wnt/β-catenin signaling in primary PanIN cells despite significantly higher levels of the total and activated Wnt cell surface coreceptor, LRP6. Vacuolar adenosine triphosphatase blockade significantly decreased the total and activated levels of EGF receptor, a determinant of PanIN progression. The activation of EGF receptor and its intracellular mediator, p44/42 mitogen-activated protein kinase, was also reduced by v-ATPase blockade. This led to diminished proliferation in response to EGF ligand. CONCLUSIONS: The v-ATPase regulates Wnt/β-catenin and EGF receptor signaling in PanINs.

21 Article Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. 2014

Rhim, Andrew D / Oberstein, Paul E / Thomas, Dafydd H / Mirek, Emily T / Palermo, Carmine F / Sastra, Stephen A / Dekleva, Erin N / Saunders, Tyler / Becerra, Claudia P / Tattersall, Ian W / Westphalen, C Benedikt / Kitajewski, Jan / Fernandez-Barrena, Maite G / Fernandez-Zapico, Martin E / Iacobuzio-Donahue, Christine / Olive, Kenneth P / Stanger, Ben Z. ·Division of Gastroenterology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Division of Digestive and Liver Diseases in the Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · Sol Goldman Pancreatic Cancer Research Center and Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA. · Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Division of Digestive and Liver Diseases in the Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA. · Division of Digestive and Liver Diseases in the Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: kenolive@columbia.edu. · Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: bstanger@exchange.upenn.edu. ·Cancer Cell · Pubmed #24856585.

ABSTRACT: Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation--features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.

22 Article Diagnosis of pernicious anemia and the risk of pancreatic cancer. 2014

Shah, Pari / Rhim, Andrew D / Haynes, Kevin / Hwang, Wei-Ting / Yang, Yu-Xiao. ·From the *Department of Medicine, Gastroenterology and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, NY; and †Division of Gastroenterology, Department of Medicine, and ‡Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. ·Pancreas · Pubmed #24622073.

ABSTRACT: OBJECTIVES: A number of studies have demonstrated a trophic effect of gastrin on pancreatic cancer cells in vitro. Pernicious anemia (PA) is a clinical condition characterized by chronic hypergastrinemia. The aim of this study was to determine if PA is a risk factor for pancreatic cancer. METHODS: This study is a retrospective cohort study using The Health Improvement Network database, which contains comprehensive health information on 7.5 million patients in the United Kingdom from 1993 to 2009. All patients with PA in the study cohort were identified and composed of the exposed group. Each exposed patient was matched on practice site, sex, and age with up to 4 unexposed patients without PA. The outcome was incident pancreatic cancer. The hazard ratio and 95% confidence intervals were estimated using multivariable Cox regression analysis. RESULTS: We identified 15,324 patients with PA and 55,094 unexposed patients. Mean follow-up time was similar between groups (exposed 4.31 [SD, 3.38] years, unexposed 4.63 [SD, 3.44] years). The multivariable adjusted hazard ratio for pancreatic cancer associated with PA was 1.16 (95% confidence interval, 0.77-1.76; P = 0.47). CONCLUSIONS: There is no significant association between PA and the risk of pancreatic cancer.

23 Article Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. 2014

Stopczynski, Rachelle E / Normolle, Daniel P / Hartman, Douglas J / Ying, Haoqiang / DeBerry, Jennifer J / Bielefeldt, Klaus / Rhim, Andrew D / DePinho, Ronald A / Albers, Kathryn M / Davis, Brian M. ·Authors' Affiliations: Departments of Neurobiology, Biostatistics, Pathology, and Medicine, University of Pittsburgh School of Medicine; Departments of Genomic Medicine and Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan. ·Cancer Res · Pubmed #24448244.

ABSTRACT: Perineural tumor invasion of intrapancreatic nerves, neurogenic inflammation, and tumor metastases along extrapancreatic nerves are key features of pancreatic malignancies. Animal studies show that chronic pancreatic inflammation produces hypertrophy and hypersensitivity of pancreatic afferents and that sensory fibers may themselves drive inflammation via neurogenic mechanisms. Although genetic mutations are required for cancer development, inflammation has been shown to be a precipitating event that can accelerate the transition of precancerous lesions to cancer. These observations led us to hypothesize that inflammation that accompanies early phases of pancreatic ductal adenocarcinoma (PDAC) would produce pathologic changes in pancreatic neurons and innervation. Using a lineage-labeled genetically engineered mouse model of PDAC, we found that pancreatic neurotrophic factor mRNA expression and sensory innervation increased dramatically when only pancreatic intraepithelial neoplasia were apparent. These changes correlated with pain-related decreases in exploratory behavior and increased expression of nociceptive genes in sensory ganglia. At later stages, cells of pancreatic origin could be found in the celiac and sensory ganglia along with metastases to the spinal cord. These results demonstrate that the nervous system participates in all stages of PDAC, including those that precede the appearance of cancer.

24 Article Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions. 2014

Rhim, Andrew D / Thege, Fredrik I / Santana, Steven M / Lannin, Timothy B / Saha, Trisha N / Tsai, Shannon / Maggs, Lara R / Kochman, Michael L / Ginsberg, Gregory G / Lieb, John G / Chandrasekhara, Vinay / Drebin, Jeffrey A / Ahmad, Nuzhat / Yang, Yu-Xiao / Kirby, Brian J / Stanger, Ben Z. ·Division of Gastroenterology, Department of Internal Medicine, Pancreatic Cancer Center, University of Michigan Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; Gastroenterology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: arhim@med.umich.edu. · Department of Biomedical Engineering, Cornell University, Ithaca, New York. · Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York. · Division of Gastroenterology, Department of Internal Medicine, Pancreatic Cancer Center, University of Michigan Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; Gastroenterology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Gastroenterology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Gastroenterology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Gastroenterology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York; Department of Medicine, Division of Hematology/Medical Oncology, Weill Cornell Medical College, New York, New York. Electronic address: kirby@cornell.edu. · Gastroenterology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: stanger@exchange.upenn.edu. ·Gastroenterology · Pubmed #24333829.

ABSTRACT: Hematogenous dissemination is thought to be a late event in cancer progression. We recently showed in a genetic model of pancreatic ductal adenocarcinoma that pancreas cells can be detected in the bloodstream before tumor formation. To confirm these findings in humans, we used microfluidic geometrically enhanced differential immunocapture to detect circulating pancreas epithelial cells in patient blood samples. We captured more than 3 circulating pancreas epithelial cells/mL in 7 of 21 (33%) patients with cystic lesions and no clinical diagnosis of cancer (Sendai criteria negative), 8 of 11 (73%) with pancreatic ductal adenocarcinoma, and in 0 of 19 patients without cysts or cancer (controls). These findings indicate that cancer cells are present in the circulation of patients before tumors are detected, which might be used in risk assessment.

25 Article Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance. 2013

Zhang, Yaqing / Yan, Wei / Collins, Meredith A / Bednar, Filip / Rakshit, Sabita / Zetter, Bruce R / Stanger, Ben Z / Chung, Ivy / Rhim, Andrew D / di Magliano, Marina Pasca. ·Authors' Affiliations: Departments of Surgery, Pathology, and Cell and Developmental Biology, Department of Internal Medicine-Gastroenterology, Michigan Center for Translational Pathology, Program in Cellular and Molecular Biology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Vascular Biology Program, Department of Surgery, Karp Family Research Laboratories, Children's Hospital, Boston, Massachusetts; Gastroenterology Division, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pharmacology, and University of Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. ·Cancer Res · Pubmed #24097820.

ABSTRACT: Pancreatic cancer, one of the deadliest human malignancies, is almost invariably associated with the presence of an oncogenic form of Kras. Mice expressing oncogenic Kras in the pancreas recapitulate the stepwise progression of the human disease. The inflammatory cytokine interleukin (IL)-6 is often expressed by multiple cell types within the tumor microenvironment. Here, we show that IL-6 is required for the maintenance and progression of pancreatic cancer precursor lesions. In fact, the lack of IL-6 completely ablates cancer progression even in presence of oncogenic Kras. Mechanistically, we show that IL-6 synergizes with oncogenic Kras to activate the reactive oxygen species detoxification program downstream of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling cascade. In addition, IL-6 regulates the inflammatory microenvironment of pancreatic cancer throughout its progression, providing several signals that are essential for carcinogenesis. Thus, IL-6 emerges as a key player at all stages of pancreatic carcinogenesis and a potential therapeutic target.

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