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Pancreatic Neoplasms: HELP
Articles by Anil K. Rustgi
Based on 29 articles published since 2010
(Why 29 articles?)
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Between 2010 and 2020, A. Rustgi wrote the following 29 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Mechanisms Underlying Metastatic Pancreatic Cancer. 2019

Pitarresi, Jason R / Rustgi, Anil K. ·Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. anil2@pennmedicine.upenn.edu. ·Adv Exp Med Biol · Pubmed #31576536.

ABSTRACT: Pancreatic ductal adenocarcinoma is an overwhelming fatal disease that often presents with overt metastases and ultimately causes the majority of cancer-associated deaths. The mechanisms underlying the metastatic cascade are complex, and research in recent years has begun to provide insights into the underlying drivers of this phenomenon. It has become clear that cancer cells, in particular pancreatic cancer cells, possess properties of plasticity involving bidirectional transition between epithelial and mesenchymal identities. Furthermore, recent work has begun to establish that there are distinct hybrid states between purely epithelial and purely mesenchymal states that cancer cells may reside, in order to thrive at different stages of carcinogenesis. We discuss how this plasticity is important for different phases of the metastatic cascade, from delamination to colonization, and how different epithelial-mesenchymal states may affect metastatic organotropism. In this review, we summarize the current understanding of pancreatic cancer cell plasticity and metastasis, and highlight current model systems that can be used to study these phenomena.

2 Review Familial pancreatic cancer: genetic advances. 2014

Rustgi, Anil K. ·Division of Gastroenterology, Department of Medicine and Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ·Genes Dev · Pubmed #24395243.

ABSTRACT: Beset by poor prognosis, pancreatic ductal adenocarcinoma is classified as familial or sporadic. This review elaborates on the known genetic syndromes that underlie familial pancreatic cancer, where there are opportunities for genetic counseling and testing as well as clinical monitoring of at-risk patients. Such subsets of familial pancreatic cancer involve germline cationic trypsinogen or PRSS1 mutations (hereditary pancreatitis), BRCA2 mutations (usually in association with hereditary breast-ovarian cancer syndrome), CDKN2 mutations (familial atypical mole and multiple melanoma), or DNA repair gene mutations (e.g., ATM and PALB2, apart from those in BRCA2). However, the vast majority of familial pancreatic cancer cases have yet to have their genetic underpinnings elucidated, waiting in part for the results of deep sequencing efforts.

3 Review A historical perspective on clinical advances in pancreatic diseases. 2013

Rustgi, Anil K. ·Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA. anil2@mail.med.upenn.edu ·Gastroenterology · Pubmed #23622134.

ABSTRACT: -- No abstract --

4 Review Pancreatic ductal cells in development, regeneration, and neoplasia. 2011

Reichert, Maximilian / Rustgi, Anil K. ·Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. ·J Clin Invest · Pubmed #22133881.

ABSTRACT: The pancreas is a complex organ comprised of three critical cell lineages: islet (endocrine), acinar, and ductal. This review will focus upon recent insights and advances in the biology of pancreatic ductal cells. In particular, emphasis will be placed upon the regulation of ductal cells by specific transcriptional factors during development as well as the underpinnings of acinar-ductal metaplasia as an important adaptive response during injury and regeneration. We also address the potential contributions of ductal cells to neoplastic transformation, specifically in pancreatic ductal adenocarcinoma.

5 Clinical Trial Mutations in the pancreatic secretory enzymes 2018

Tamura, Koji / Yu, Jun / Hata, Tatsuo / Suenaga, Masaya / Shindo, Koji / Abe, Toshiya / MacGregor-Das, Anne / Borges, Michael / Wolfgang, Christopher L / Weiss, Matthew J / He, Jin / Canto, Marcia Irene / Petersen, Gloria M / Gallinger, Steven / Syngal, Sapna / Brand, Randall E / Rustgi, Anil / Olson, Sara H / Stoffel, Elena / Cote, Michele L / Zogopoulos, George / Potash, James B / Goes, Fernando S / McCombie, Richard W / Zandi, Peter P / Pirooznia, Mehdi / Kramer, Melissa / Parla, Jennifer / Eshleman, James R / Roberts, Nicholas J / Hruban, Ralph H / Klein, Alison Patricia / Goggins, Michael. ·Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Health Sciences Research, Mayo Clinic, Rochester, MN 55905. · Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5. · Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA 02215. · Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213. · Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Pancreatic Cancer Translational Center of Excellence, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017. · Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109. · Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201. · The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9. · The Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. · InGenious Targeting Laboratory, Ronkonkoma, NY 11779. · Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; mgoggins@jhmi.edu. ·Proc Natl Acad Sci U S A · Pubmed #29669919.

ABSTRACT: To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of

6 Article Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. 2020

Goggins, Michael / Overbeek, Kasper Alexander / Brand, Randall / Syngal, Sapna / Del Chiaro, Marco / Bartsch, Detlef K / Bassi, Claudio / Carrato, Alfredo / Farrell, James / Fishman, Elliot K / Fockens, Paul / Gress, Thomas M / van Hooft, Jeanin E / Hruban, R H / Kastrinos, Fay / Klein, Allison / Lennon, Anne Marie / Lucas, Aimee / Park, Walter / Rustgi, Anil / Simeone, Diane / Stoffel, Elena / Vasen, Hans F A / Cahen, Djuna L / Canto, Marcia Irene / Bruno, Marco / Anonymous1461018. ·Pathology, Medicine Oncology, Johns Hopkins University, Baltimore, Maryland, USA mgoggins@jhmi.edu. · Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. · GI Cancer Genetics and Prevention Program, Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA. · Department of Surgery, Division of Surgical Oncology, Denver, Colorado, USA. · Division of Visceral, Thoracic and Vascular Surgery, University of Marburg, Marburg, Germany. · Department of Surgey, University of Verona, Verona, Italy. · Medical Oncology, Hospital Ramón y Cajal, Madrid, Spain. · Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. · The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, Maryland, USA. · Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology & Metabolism, Amsterdam, The Netherlands. · Gastroenterology, Endocrinology, Metabolism and Infectiology, University of Marburg, Marburg, Germany. · Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands. · Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. · Division of Digestive and Liver Diseases, Columbia University Medical Center, New York City, New York, USA. · Division of Digestive and Liver Diseases, Columbia University, New York City, New York, USA. · Oncology, Johns Hopkins University, Baltimore, Maryland, USA. · Medicine, Johns Hopkins University, Baltimore, Maryland, USA. · Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA. · New York University Medical Center, New York City, New York, USA. · University of Michigan, Ann Arbor, Michigan, USA. · Gastroenterology and Hepatology, Leiden University, Leiden, The Netherlands. ·Gut · Pubmed #31672839.

ABSTRACT: BACKGROUND AND AIM: The International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals). METHODS: A modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed. RESULTS: Consensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline CONCLUSIONS: Pancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation.

7 Article A region-based gene association study combined with a leave-one-out sensitivity analysis identifies SMG1 as a pancreatic cancer susceptibility gene. 2019

Wong, Cavin / Chen, Fei / Alirezaie, Najmeh / Wang, Yifan / Cuggia, Adeline / Borgida, Ayelet / Holter, Spring / Lenko, Tatiana / Domecq, Celine / Anonymous2511041 / Petersen, Gloria M / Syngal, Sapna / Brand, Randall / Rustgi, Anil K / Cote, Michele L / Stoffel, Elena / Olson, Sara H / Roberts, Nicholas J / Akbari, Mohammad R / Majewski, Jacek / Klein, Alison P / Greenwood, Celia M T / Gallinger, Steven / Zogopoulos, George. ·The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. · The Goodman Cancer Research Centre of McGill University, Montreal, Quebec, Canada. · Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America. · McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America. · Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical Schozol, Boston, Massachusetts, United States of America. · Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. · Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translation Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America. · Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, United States of America. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America. · Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States of America. · The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America. · Women's College Hospital Research Institute, Women's College Hospital, Toronto, Ontario, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. · Ludmer Centre for Neuroinformatics & Mental Health, McGill University, Montreal, Quebec, Canada. · Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada. · Gerald Bronfman Department of Oncology, and Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada. ·PLoS Genet · Pubmed #31469826.

ABSTRACT: Pancreatic adenocarcinoma (PC) is a lethal malignancy that is familial or associated with genetic syndromes in 10% of cases. Gene-based surveillance strategies for at-risk individuals may improve clinical outcomes. However, familial PC (FPC) is plagued by genetic heterogeneity and the genetic basis for the majority of FPC remains elusive, hampering the development of gene-based surveillance programs. The study was powered to identify genes with a cumulative pathogenic variant prevalence of at least 3%, which includes the most prevalent PC susceptibility gene, BRCA2. Since the majority of known PC susceptibility genes are involved in DNA repair, we focused on genes implicated in these pathways. We performed a region-based association study using the Mixed-Effects Score Test, followed by leave-one-out characterization of PC-associated gene regions and variants to identify the genes and variants driving risk associations. We evaluated 398 cases from two case series and 987 controls without a personal history of cancer. The first case series consisted of 109 patients with either FPC (n = 101) or PC at ≤50 years of age (n = 8). The second case series was composed of 289 unselected PC cases. We validated this discovery strategy by identifying known pathogenic BRCA2 variants, and also identified SMG1, encoding a serine/threonine protein kinase, to be significantly associated with PC following correction for multiple testing (p = 3.22x10-7). The SMG1 association was validated in a second independent series of 532 FPC cases and 753 controls (p<0.0062, OR = 1.88, 95%CI 1.17-3.03). We showed segregation of the c.4249A>G SMG1 variant in 3 affected relatives in a FPC kindred, and we found c.103G>A to be a recurrent SMG1 variant associating with PC in both the discovery and validation series. These results suggest that SMG1 is a novel PC susceptibility gene, and we identified specific SMG1 gene variants associated with PC risk.

8 Article PRRX1 isoforms cooperate with FOXM1 to regulate the DNA damage response in pancreatic cancer cells. 2019

Marchand, Benoît / Pitarresi, Jason R / Reichert, Maximilian / Suzuki, Kensuke / Laczkó, Dorottya / Rustgi, Anil K. ·Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. · Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. · II. Medizinische Klinik, Technical University of Munich, 81675, Munich, Germany. · Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. · Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. anil2@pennmedicine.upenn.edu. · Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. anil2@pennmedicine.upenn.edu. · Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. anil2@pennmedicine.upenn.edu. ·Oncogene · Pubmed #30705403.

ABSTRACT: PRRX1 is a homeodomain transcriptional factor, which has two isoforms, PRXX1A and PRRX1B. The PRRX1 isoforms have been demonstrated to be important in pancreatic cancer, especially in the regulation of epithelial-to-mesenchymal transition (EMT) in Pancreatic Ductal Adenocarcinoma (PDAC) and of mesenchymal-to-epithelial transition (MET) in liver metastasis. In order to determine the functional underpinnings of PRRX1 and its isoforms, we have unraveled a new interplay between PRRX1 and the FOXM1 transcriptional factors. Our detailed biochemical analysis reveals the direct physical interaction between PRRX1 and FOXM1 proteins that requires the PRRX1A/B 200-222/217 amino acid (aa) region and the FOXM1 Forkhead domain. Additionally, we demonstrate the cooperation between PRRX1 and FOXM1 in the regulation of FOXM1-dependent transcriptional activity. Moreover, we establish FOXM1 as a critical downstream target of PRRX1 in pancreatic cancer cells. We demonstrate a novel role for PRRX1 in the regulation of genes involved in DNA repair pathways. Indeed, we show that expression of PRRX1 isoforms may limit the induction of DNA damage in pancreatic cancer cells. Finally, we demonstrate that targeting FOXM1 with the small molecule inhibitor FDI6 suppress pancreatic cancer cell proliferation and induces their apoptotic cell death. FDI6 sensitizes pancreatic cancer cells to Etoposide and Gemcitabine induced apoptosis. Our data provide new insights into PRRX1's involvement in regulating DNA damage and provide evidence of a possible PRRX1-FOXM1 axis that is critical for PDAC cells.

9 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

10 Article A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors. 2018

Alvarez, Mariano J / Subramaniam, Prem S / Tang, Laura H / Grunn, Adina / Aburi, Mahalaxmi / Rieckhof, Gabrielle / Komissarova, Elena V / Hagan, Elizabeth A / Bodei, Lisa / Clemons, Paul A / Dela Cruz, Filemon S / Dhall, Deepti / Diolaiti, Daniel / Fraker, Douglas A / Ghavami, Afshin / Kaemmerer, Daniel / Karan, Charles / Kidd, Mark / Kim, Kyoung M / Kim, Hee C / Kunju, Lakshmi P / Langel, Ülo / Li, Zhong / Lee, Jeeyun / Li, Hai / LiVolsi, Virginia / Pfragner, Roswitha / Rainey, Allison R / Realubit, Ronald B / Remotti, Helen / Regberg, Jakob / Roses, Robert / Rustgi, Anil / Sepulveda, Antonia R / Serra, Stefano / Shi, Chanjuan / Yuan, Xiaopu / Barberis, Massimo / Bergamaschi, Roberto / Chinnaiyan, Arul M / Detre, Tony / Ezzat, Shereen / Frilling, Andrea / Hommann, Merten / Jaeger, Dirk / Kim, Michelle K / Knudsen, Beatrice S / Kung, Andrew L / Leahy, Emer / Metz, David C / Milsom, Jeffrey W / Park, Young S / Reidy-Lagunes, Diane / Schreiber, Stuart / Washington, Kay / Wiedenmann, Bertram / Modlin, Irvin / Califano, Andrea. ·Department of Systems Biology, Columbia University, New York, NY, USA. · DarwinHealth Inc, New York, NY, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA. · Department of Urology, Columbia University, New York, NY, USA. · Division of Pathology, European Institute of Oncology, Milan, Italy. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. · Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · PsychoGenics Inc., Tarrytown, NY, USA. · Department of General and Visceral Surgery, Zentralklinik, Bad Berka, Germany. · Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA. · Wren Laboratories, Branford, CT, USA. · Division of Hematology Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. · Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. · Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Neurochemistry, the Arrhenius Laboratories for Nat. Sci., Stockholm University, Stockholm, Sweden. · Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Tartu, Estonia. · Falconwood Foundation, New York, NY, USA. · Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria. · Department of Pathology, Columbia University, New York, NY, USA. · Department of Pathology, University Health Network, University of Toronto, Toronto, Canada. · Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA. · Division of Colon and Rectal Surgery, State University of New York, Stony Brook, NY, USA. · Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA. · Imperial College London, London, UK. · Medical Oncology, National Center for Tumor Diseases Heidelberg, University Medical Center Heidelberg, Heidelberg, Germany. · Mount Sinai School of Medicine, New York, NY, USA. · Department of Surgery, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA. · Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. · Department of Internal Medicine, Division of Gastroenterology, Charite, Universitätsmedizin Berlin, Berlin, Germany. · Emeritus Professor Gastrointestinal Surgery, School of Medicine, Yale University, New Haven, Connecticut, USA. imodlin@irvinmodlin.com. · Department of Systems Biology, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · Department of Biomedical Informatics, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · J.P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. ·Nat Genet · Pubmed #29915428.

ABSTRACT: We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.

11 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.

12 Article The TALE homeodomain transcription factor MEIS1 activates the pro-metastatic melanoma cell adhesion molecule Mcam to promote migration of pancreatic cancer cells. 2017

von Burstin, Johannes / Bachhuber, Friedrich / Paul, Mariel / Schmid, Roland M / Rustgi, Anil K. ·Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. · I. Medizinische Klinik, Technische Universität München, Munich, Germany. · II. Medizinische Klinik, Technische Universität München, Munich, Germany. ·Mol Carcinog · Pubmed #27583552.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly types of cancer, and the majority of pancreatic cancer deaths is caused by metastasis. Therapeutic options for systemic disease are limited, in particular due to the heterogeneous events leading to tumor dissemination. Previous studies highlighted an association of the homeodomain transcription factor MEIS1 with a ductal phenotype in pancreatic tissue architecture. Using immunohistochemistry, we demonstrate that MEIS1 is expressed in aberrant duct structures of Ela-TGFα transgenic mice as well as in pancreatic intraepithelial neoplasia (PanINs), primary PDAC, and metastatic disease in Ptf1a

13 Article Pancreatic fibroblasts smoothen their activities via AKT-GLI2-TGFα. 2016

Rustgi, Anil K. ·Division of Gastroenterology, Department of Medicine, Department of Genetics, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA. ·Genes Dev · Pubmed #27664234.

ABSTRACT: Pancreatic stromal fibroblasts provide structural support. Activated fibroblasts are critical in the tumor microenvironment. In this issue of Genes & Development, Liu and colleagues (pp. 1943-1955) unravel the finding that depletion of Smoothened (Smo) in pancreatic stromal fibroblasts results in AKT activation and noncanonical GLI2 activation with subsequent TGFα secretion, activation of EGFR in pancreatic epithelial cells, and augmentation of acinar-ductal metaplasia. Additionally, Smo-mediated signaling has proproliferative effects on pancreatic tumor cells.

14 Article ETS-Transcription Factor ETV1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer. 2016

Heeg, Steffen / Das, Koushik K / Reichert, Maximilian / Bakir, Basil / Takano, Shigetsugu / Caspers, Julia / Aiello, Nicole M / Wu, Katherine / Neesse, Albrecht / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Hicks, Philip / Rustgi, Anil K. ·Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; 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 Medicine II, Medical Center, University of Freiburg; Freiburg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; II. Medizinische Klinik, Technical University of Munich, Munich, Germany. · Department of Medicine II, Medical Center, University of Freiburg; Freiburg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Division of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Goettingen, Goettingen, Germany. · University of Texas, MD Anderson Cancer Center, Houston, Texas. · David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; 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 Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: anil2@mail.med.upenn.edu. ·Gastroenterology · Pubmed #27318148.

ABSTRACT: BACKGROUND & AIMS: The ETS-transcription factor ETV1 is involved in epithelial-mesenchymal transition during pancreatic development and is induced in mouse pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). We investigated the function of ETV1 in stromal expansion of PDAC and metastasis, as well as its effects on a novel downstream target Sparc, which encodes a matricellular protein found in PDAC stroma that has been associated with invasiveness, metastasis and poor patient outcomes. METHODS: Pancreatic ductal cells were isolated from Pdx1Cre;Kras(G12D/+) mice (PanIN), Pdx1Cre;Kras(G12D/+);p53(fl/+) and Pdx1Cre;Kras(G12D/+);p53(fl/+);Rosa26(YFP) mice (PDAC), and Pdx1Cre;Kras(G12D/+);p53(fl/+);Sparc(-/-) mice. Cells were grown in 3-dimensional organoid culture to analyze morphology, proliferation, and invasion. Human PanIN and PDAC tissues were evaluated for ETV1 expression. Orthotopic pancreatic transplants of ETV1-overexpressing PDAC and respective control cells were performed. RESULTS: ETV1 expression was significantly increased in human PanINs and, even more so, in primary and metastatic PDAC. Analyses of mouse orthotopic xenografts revealed that ETV1 induced significantly larger primary tumors than controls, with significantly increased stromal expansion, ascites and metastases. In 3-dimensional organoids, ETV1 disrupted cyst architecture, induced EMT, and increased invasive capacity. Furthermore, we identified Sparc as a novel functional gene target of Etv1 by luciferase assays, and SPARC and ETV1 proteins co-localized in vivo. Disruption of Sparc abrogates the phenotype of stromal expansion and metastasis found with ETV1 overexpression in vivo. We identified hyaluronan synthase 2 (Has2) as another novel downstream factor of Etv1; that may mediate ETV1's significant expansion of hyaluronic acid in PDAC stroma. Conversely, disruption of Etv1 in PDAC mice (Pdx1Cre;Kras(G12D/+);p53(fl/+);Rosa26(YFP);Cre;Etv1(fl/fl)) reduced levels of SPARC and hyaluronic acid in the stroma. CONCLUSIONS: ETV1 is critical in the desmoplastic stromal expansion and metastatic progression of pancreatic cancer in mice, mediated functionally in part through Sparc and Has2.

15 Article Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis. 2016

Westphalen, C Benedikt / Takemoto, Yoshihiro / Tanaka, Takayuki / Macchini, Marina / Jiang, Zhengyu / Renz, Bernhard W / Chen, Xiaowei / Ormanns, Steffen / Nagar, Karan / Tailor, Yagnesh / May, Randal / Cho, Youngjin / Asfaha, Samuel / Worthley, Daniel L / Hayakawa, Yoku / Urbanska, Aleksandra M / Quante, Michael / Reichert, Maximilian / Broyde, Joshua / Subramaniam, Prem S / Remotti, Helen / Su, Gloria H / Rustgi, Anil K / Friedman, Richard A / Honig, Barry / Califano, Andrea / Houchen, Courtney W / Olive, Kenneth P / Wang, Timothy C. ·Department of Internal Medicine III, Hospital of the University of Munich D-81377, Munich, Germany; Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, 40128 Bologna, Italy. · Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich D-81377, Munich, Germany; Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology, Hospital of the University of Munich D-81377, Munich, Germany. · Department of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, OK 73104, USA. · Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Internal Medicine II, Klinikum rechts der Isar II, Technische Universität München, D-81675 Munich, Germany. · Department of Internal Medicine II, Klinikum rechts der Isar II, Technische Universität München, D-81675 Munich, Germany; Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. · Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Otolaryngology / Head & Neck Surgery, Columbia University Medical Center, New York, NY 10032, USA. · Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Otolaryngology / Head & Neck Surgery, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA; Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Center for Computational Biology and Bioinformatics (C2B2), Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu. ·Cell Stem Cell · Pubmed #27058937.

ABSTRACT: The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer.

16 Article Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization. 2016

Takano, Shigetsugu / Reichert, Maximilian / Bakir, Basil / Das, Koushik K / Nishida, Takahiro / Miyazaki, Masaru / Heeg, Steffen / Collins, Meredith A / Marchand, Benoît / Hicks, Philip D / Maitra, Anirban / Rustgi, Anil K. ·Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; II. Medizinische Klinik, Technical University of Munich, Munich 81675, Germany; · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; · Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine II, Medical Center, University of Freiburg, 79106 Freiburg, Germany; · Department of Pathology, Sheikh Ahmad bin Zayed Al Nahyan Pancreatic Cancer Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Translational Molecular Pathology, Sheikh Ahmad bin Zayed Al Nahyan Pancreatic Cancer Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ·Genes Dev · Pubmed #26773005.

ABSTRACT: The two major isoforms of the paired-related homeodomain transcription factor 1 (Prrx1), Prrx1a and Prrx1b, are involved in pancreatic development, pancreatitis, and carcinogenesis, although the biological role that these isoforms serve in the systemic dissemination of pancreatic ductal adenocarcinoma (PDAC) has not been investigated. An epithelial-mesenchymal transition (EMT) is believed to be important for primary tumor progression and dissemination, whereas a mesenchymal-epithelial transition (MET) appears crucial for metastatic colonization. Here, we describe novel roles for both isoforms in the metastatic cascade using complementary in vitro and in vivo models. Prrx1b promotes invasion, tumor dedifferentiation, and EMT. In contrast, Prrx1a stimulates metastatic outgrowth in the liver, tumor differentiation, and MET. We further demonstrate that the switch from Prrx1b to Prrx1a governs EMT plasticity in both mouse models of PDAC and human PDAC. Last, we identify hepatocyte growth factor ( HGF) as a novel transcriptional target of Prrx1b. Targeted therapy of HGF in combination with gemcitabine in a preclinical model of PDAC reduces primary tumor volume and eliminates metastatic disease. Overall, we provide new insights into the isoform-specific roles of Prrx1a and Prrx1b in primary PDAC formation, dissemination, and metastatic colonization, allowing for novel therapeutic strategies targeting EMT plasticity.

17 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.

18 Article Impact of Metformin on Advanced Pancreatic Cancer Survival: Too Little, Too Late? 2016

Yang, Yu-Xiao / Rustgi, Anil K. ·Division of Gastroenterology and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. yangy@mail.med.upenn.edu. · Division of Gastroenterology and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. ·Clin Cancer Res · Pubmed #26637275.

ABSTRACT: Metformin offers no survival advantage in patients with metastatic pancreatic cancer. Despite promising experimental evidence suggesting an antitumor effect of metformin, its impact on the survival of advanced pancreatic cancer is likely very limited. Future studies may need to consider its role in early-stage pancreatic cancer. See related article by Reni et al., p. 1076.

19 Article Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells. 2016

Diersch, S / Wirth, M / Schneeweis, C / Jörs, S / Geisler, F / Siveke, J T / Rad, R / Schmid, R M / Saur, D / Rustgi, A K / Reichert, M / Schneider, G. ·II. Medizinische Klinik, Technische Universität München, München, Germany. · Division of Translational Solid Tumor Oncology, German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 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, Philadelphia, PA, USA. ·Oncogene · Pubmed #26592448.

ABSTRACT: Epidermal growth factor receptor (EGFR) signaling has a critical role in oncogenic Kras-driven pancreatic carcinogenesis. However, the downstream targets of this signaling network are largely unknown. We developed a novel model system utilizing murine primary pancreatic ductal epithelial cells (PDECs), genetically engineered to allow time-specific expression of oncogenic Kras(G12D) from the endogenous promoter. We show that primary PDECs are susceptible to Kras(G12D)-driven transformation and form pancreatic ductal adenocarcinomas in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of Kras(G12D) induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease Kras(G12D)-activated ERK or PI3K signaling. Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC. EGFR and c-MYC have been shown to be essential for pancreatic carcinogenesis. Importantly, our data link both pathways and thereby explain the crucial role of EGFR for Kras(G12D)-driven carcinogenesis in the pancreas.

20 Article Detection of Tumor Suppressor Genes in Cancer Development by a Novel shRNA-Based Method. 2015

von Burstin, Johannes / Diersch, Sandra / Schneider, Günter / Reichert, Maximilian / Rustgi, Anil K / Schmid, Roland M. ·II. Medizinische Klinik, Technische Universität München, Munich, Germany. johannes.von-burstin@lrz.tum.de. · II. Medizinische Klinik, Technische Universität München, Munich, Germany. · II. Medizinische Klinik, Technische Universität München, Munich, Germany. Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. · Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. ·Mol Cancer Res · Pubmed #25724428.

ABSTRACT: IMPLICATIONS: The combinatory in vitro/in vivo approach described in this study allows for rapid and efficient identification of genes involved in carcinogenesis and opens new avenues for the development of therapeutic strategies to improve cancer treatment.

21 Article ERK2-regulated TIMP1 induces hyperproliferation of K-Ras(G12D)-transformed pancreatic ductal cells. 2013

Botta, Gregory P / Reichert, Maximilian / Reginato, Mauricio J / Heeg, Steffen / Rustgi, Anil K / Lelkes, Peter I. ·Department of Biochemistry and Molecular Biology, Molecular and Cellular Biology and Genetics Program, Drexel University College of Medicine, Philadelphia, PA, USA. ·Neoplasia · Pubmed #23555182.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) commonly contains a mutation in K-Ras(G12D) and is characterized by a desmoplastic reaction composed of deregulated, proliferating cells embedded in an abnormal extracellular matrix (ECM). Our previous observations imply that inhibiting the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK2) kinase signal pathway reverses a matrix metalloproteinase 1-specific invasive phenotype. Here, we investigated the specific genes downstream of MAPK-ERK2 responsible for the hyperproliferative abilities of human and murine primary ductal epithelial cells (PDCs) within an ECM. Compared with control, DNA synthesis and total cell proliferation was significantly increased in human PDCs harboring the PDAC common p53, Rb/p16(INK4a), and K-Ras (G12D) mutations. Both of these effects were readily reversed following small-molecule inhibition or lentiviral silencing of ERK2. Microarray analysis of PDCs in three-dimensional (3D) culture revealed a unique, MAPK-influenced gene signature downstream of K-Ras (G12D). Unbiased hierarchical analysis permitted filtration of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). Pancreatic cells isolated from Pdx1-Cre; LSL-K-ras(G12D/+)-mutated mice exhibit increased TIMP1 RNA transcription compared to wild-type littermate controls. Analyses of both 3D, in vitro human K-Ras (G12D) PDCs and data mining of publicly annotated human pancreatic data sets correlatively indicate increased levels of TIMP1 RNA. While silencing TIMP1 did not significantly effect PDC proliferation, exogenous addition of human recombinant TIMP1 significantly increased proliferation but only in transformed K-Ras (G12D) PDCs in 3D. Overall, TIMP1 is an upregulated gene product and a proliferative inducer of K-Ras(G12D)-mutated PDCs through the ERK2 signaling pathway.

22 Article Imbalance of desmoplastic stromal cell numbers drives aggressive cancer processes. 2013

Kadaba, Raghu / Birke, Hanna / Wang, Jun / Hooper, Steven / Andl, Claudia D / Di Maggio, Francesco / Soylu, Erdinc / Ghallab, Mohammed / Bor, Daniel / Froeling, Fieke Em / Bhattacharya, Satyajit / Rustgi, Anil K / Sahai, Erik / Chelala, Claude / Sasieni, Peter / Kocher, Hemant M. ·Centre for Tumour Biology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK. ·J Pathol · Pubmed #23359139.

ABSTRACT: Epithelial tissues have sparse stroma, in contrast to their corresponding tumours. The effect of cancer cells on stromal cells is well recognized. Increasingly, stromal components, such as endothelial and immune cells, are considered indispensable for cancer progression. The role of desmoplastic stroma, in contrast, is poorly understood. Targeting such cellular components within the tumour is attractive. Recent evidence strongly points towards a dynamic stromal cell participation in cancer progression that impacts patient prognosis. The role of specific desmoplastic stromal cells, such as stellate cells and myofibroblasts in pancreatic, oesophageal and skin cancers, was studied in bio-engineered, physiomimetic organotypic cultures and by regression analysis. For pancreatic cancer, the maximal effect on increasing cancer cell proliferation and invasion, as well as decreasing cancer cell apoptosis, occurs when stromal (pancreatic stellate cells) cells constitute the majority of the cellular population (maximal effect at a stromal cell proportion of 0.66-0.83), accompanied by change in expression of key molecules such as E-cadherin and β-catenin. Gene-expression microarrays, across three tumour types, indicate that stromal cells consistently and significantly alter global cancer cell functions such as cell cycle, cell-cell signalling, cell movement, cell death and inflammatory response. However, these changes are mediated through cancer type-specific alteration of expression, with very few common targets across tumour types. As highlighted by these in vitro data, the reciprocal relationship of E-cadherin and polymeric immunoglobulin receptor (PIGR) expression in cancer cells could be shown, in vivo, to be dependent on the stromal content of human pancreatic cancer. These studies demonstrate that context-specific cancer-stroma crosstalk requires to be precisely defined for effective therapeutic targeting. These data may be relevant to non-malignant processes where epithelial cells interact with stromal cells, such as chronic inflammatory and fibrotic conditions.

23 Article The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis. 2013

Reichert, Maximilian / Takano, Shigetsugu / von Burstin, Johannes / Kim, Sang-Bae / Lee, Ju-Seog / Ihida-Stansbury, Kaori / Hahn, Christopher / Heeg, Steffen / Schneider, Günter / Rhim, Andrew D / Stanger, Ben Z / Rustgi, Anil K. ·Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, USA. ·Genes Dev · Pubmed #23355395.

ABSTRACT: Pancreatic exocrine cell plasticity can be observed during development, pancreatitis with subsequent regeneration, and also transformation. For example, acinar-ductal metaplasia (ADM) occurs during acute pancreatitis and might be viewed as a prelude to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) development. To elucidate regulatory processes that overlap ductal development, ADM, and the progression of normal cells to PanIN lesions, we undertook a systematic approach to identify the Prrx1 paired homeodomain Prrx1 transcriptional factor as a highly regulated gene in these processes. Prrx1 annotates a subset of pancreatic ductal epithelial cells in Prrx1creER(T2)-IRES-GFP mice. Furthermore, sorted Prrx1(+) cells have the capacity to self-renew and expand during chronic pancreatitis. The two isoforms, Prrx1a and Prrx1b, regulate migration and invasion, respectively, in pancreatic cancer cells. In addition, Prrx1b is enriched in circulating pancreatic cells (Pdx1cre;LSL-Kras(G12D/+);p53(fl/+);R26YFP). Intriguingly, the Prrx1b isoform, which is also induced in ADM, binds the Sox9 promoter and positively regulates Sox9 expression. This suggests a new hierarchical scheme whereby a Prrx1-Sox9 axis may influence the emergence of acinar-ductal metaplasia and regeneration. Furthermore, our data provide a possible explanation of why pancreatic cancer is skewed toward a ductal fate.

24 Article EMT and dissemination precede pancreatic tumor formation. 2012

Rhim, Andrew D / Mirek, Emily T / Aiello, Nicole M / Maitra, Anirban / Bailey, Jennifer M / McAllister, Florencia / Reichert, Maximilian / Beatty, Gregory L / Rustgi, Anil K / Vonderheide, Robert H / Leach, Steven D / Stanger, Ben Z. ·Gastroenterology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. ·Cell · Pubmed #22265420.

ABSTRACT: Metastasis is the leading cause of cancer-associated death but has been difficult to study because it involves a series of rare, stochastic events. To capture these events, we developed a sensitive method to tag and track pancreatic epithelial cells in a mouse model of pancreatic cancer. Tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-to-mesenchymal transition (EMT). Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.

25 Article Constitutive K-RasG12D activation of ERK2 specifically regulates 3D invasion of human pancreatic cancer cells via MMP-1. 2012

Botta, Gregory P / Reginato, Mauricio J / Reichert, Maximilian / Rustgi, Anil K / Lelkes, Peter I. ·Department of Biochemistry and Molecular BiologyDrexel University College of Medicine, Philadelphia, Pennsylvania, USA. ·Mol Cancer Res · Pubmed #22160930.

ABSTRACT: Pancreatic ductal adenocarcinomas (PDAC) are highly invasive and metastatic neoplasms commonly unresponsive to current drug therapy. Overwhelmingly, PDAC harbors early constitutive, oncogenic mutations in K-Ras(G12D) that exist prior to invasion. Histologic and genetic analyses of human PDAC biopsies also exhibit increased expression of extracellular signal-regulated kinase (ERK) 1/2 and proinvasive matrix metalloproteinases (MMP), indicators of poor prognosis. However, the distinct molecular mechanisms necessary for K-Ras/ERK1/2 signaling and its influence on MMP-directed stromal invasion in primary human pancreatic ductal epithelial cells (PDEC) have yet to be elucidated in three-dimensions. Expression of oncogenic K-Ras(G12D) alone in genetically defined PDECs reveals increased invadopodia and epithelial-to-mesenchymal transition markers, but only when cultured in a three-dimensional model incorporating a basement membrane analog. Activation of ERK2, but not ERK1, also occurs only in K-Ras(G12D)-mutated PDECs cultured in three-dimensions and is a necessary intracellular signaling event for invasion based upon pharmacologic and short hairpin RNA (shRNA) inhibition. Increased active invasion of K-Ras(G12D) PDECs through the basement membrane model is associated with a specific microarray gene expression signature and induction of MMP endopeptidases. Specifically, MMP-1 RNA, its secreted protein, and its proteolytic cleavage activity are amplified in K-Ras(G12D) PDECs when assayed by real-time quantitative PCR, ELISA, and fluorescence resonance energy transfer (FRET). Importantly, shRNA silencing of MMP-1 mimics ERK2 inhibition and disrupts active, vertical PDEC invasion. ERK2 isoform and MMP-1 targeting are shown to be viable strategies to attenuate invasion of K-Ras(G12D)-mutated human pancreatic cancer cells in a three-dimensional tumor microenvironment.

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