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Pancreatic Neoplasms: HELP
Articles by Matthias Hebrok
Based on 23 articles published since 2010
(Why 23 articles?)
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Between 2010 and 2020, Matthias Hebrok wrote the following 23 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Regulation of Cellular Identity in Cancer. 2015

Roy, Nilotpal / Hebrok, Matthias. ·Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143, USA. · Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143, USA. Electronic address: mhebrok@diabetes.ucsf.edu. ·Dev Cell · Pubmed #26702828.

ABSTRACT: Neoplastic transformation requires changes in cellular identity. Emerging evidence increasingly points to cellular reprogramming, a process during which fully differentiated and functional cells lose aspects of their identity while gaining progenitor characteristics, as a critical early step during cancer initiation. This cell identity crisis persists even at the malignant stage in certain cancers, suggesting that reactivation of progenitor functions supports tumorigenicity. Here, we review recent findings that establish the essential role of cellular reprogramming during neoplastic transformation and the major players involved in it with a special emphasis on pancreatic cancer.

2 Review Control of cell identity in pancreas development and regeneration. 2013

Stanger, Ben Z / Hebrok, Matthias. ·Division of Gastroenterology, Department of Medicine, Department of Cell and Developmental Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. bstanger@exchange.upenn.edu ·Gastroenterology · Pubmed #23622126.

ABSTRACT: The endocrine and exocrine cells in the adult pancreas are not static, but can change their differentiation state in response to injury or stress. This concept of cells in flux means that there may be ways to generate certain types of cells (such as insulin-producing β-cells) and prevent formation of others (such as transformed neoplastic cells). We review different aspects of cell identity in the pancreas, discussing how cells achieve their identity during embryonic development and maturation, and how this identity remains plastic, even in the adult pancreas.

3 Review KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. 2010

Morris, John P / Wang, Sam C / Hebrok, Matthias. ·Diabetes Center, University of California, San Francisco, 513 Parnassus Ave, San Francisco, California 94143, USA. ·Nat Rev Cancer · Pubmed #20814421.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by near-universal mutations in KRAS and frequent deregulation of crucial embryonic signalling pathways, including the Hedgehog (Hh) and Wnt-β-catenin cascades. The creation of mouse models that closely resemble the human disease has provided a platform to better understand when and in which cell types these pathways are misregulated during PDAC development. Here we examine the central part that KRAS plays in the biology of PDAC, and how the timing and location of Hh and Wnt-β-catenin signalling dictate the specification and oncogenic properties of PDAC.

4 Review Cellular plasticity within the pancreas--lessons learned from development. 2010

Puri, Sapna / Hebrok, Matthias. ·Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143, USA. ·Dev Cell · Pubmed #20230744.

ABSTRACT: The pancreas has been the subject of intense research due to the debilitating diseases that result from its dysfunction. In this review, we summarize current understanding of the critical tissue interactions and intracellular regulatory events that take place during formation of the pancreas from a small cluster of cells in the foregut domain of the mouse embryo. Importantly, an understanding of principles that govern the development of this organ has equipped us with the means to manipulate both embryonic and differentiated adult cells in the context of regenerative medicine. The emerging area of lineage modulation within the adult pancreas is of particular interest, and this review summarizes recent findings that exemplify how lessons learned from development are being applied to reveal the potential of fully differentiated cells to change fate.

5 Article The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis. 2018

Tsuda, Motoyuki / Fukuda, Akihisa / Roy, Nilotpal / Hiramatsu, Yukiko / Leonhardt, Laura / Kakiuchi, Nobuyuki / Hoyer, Kaja / Ogawa, Satoshi / Goto, Norihiro / Ikuta, Kozo / Kimura, Yoshito / Matsumoto, Yoshihide / Takada, Yutaka / Yoshioka, Takuto / Maruno, Takahisa / Yamaga, Yuichi / Kim, Grace E / Akiyama, Haruhiko / Ogawa, Seishi / Wright, Christopher V / Saur, Dieter / Takaori, Kyoichi / Uemoto, Shinji / Hebrok, Matthias / Chiba, Tsutomu / Seno, Hiroshi. ·Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Diabetes Center, Department of Medicine, UCSF, San Francisco, California, USA. · Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Hematology, Oncology and Tumorimmunology, Charite-Universitätsmedizin Berlin, Berlin, Germany. · Department of Pathology, UCSF, San Francisco, California, USA. · Department of Orthopaedics, Gifu University, Gifu, Japan. · Program in Developmental Biology and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. · Department of Internal Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Kansai Electric Power Hospital, Osaka, Japan. ·J Clin Invest · Pubmed #30010625.

ABSTRACT: Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.

6 Article Atypical flat lesions derive from pancreatic acinar cells. 2017

von Figura, Guido / Fahrenkrog-Petersen, Leonie / Hidalgo-Sastre, Ana / Hartmann, Daniel / Hüser, Norbert / Schmid, Roland M / Hebrok, Matthias / Roy, Nilotpal / Esposito, Irene. ·II Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. Electronic address: gvfigura@tum.de. · II Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. · Chirurgische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. · Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. · Institute of Pathology, University Clinic Duesseldorf, Heinrich-Heine University, Duesseldorf, Germany. ·Pancreatology · Pubmed #28473229.

ABSTRACT: OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is thought to derive from different precursor lesions including the recently identified atypical flat lesions (AFL). While all precursor lesions and PDAC share ductal characteristics, there is an ongoing debate about the cellular origin of the different PDAC precursor lesions. In particular, pancreatic acinar cells have previously been shown to display a remarkable plasticity being able to undergo ductal dedifferentiation in the context of oncogenic stimuli. METHODS: Histological analyses were performed in a murine PDAC model that specifically expresses oncogenic Kras in adult pancreatic acinar cells. Occurrence, characterization, and lineage tracing of AFLs were investigated. RESULTS: Upon expression of oncogenic Kras in adult pancreatic acinar cells, AFLs with typical morphology and expression profile arise. Lineage tracing confirmed that the AFLs were of acinar origin. CONCLUSIONS: Using a murine PDAC model, this study identifies pancreatic acinar cells as a cellular source for AFLs.

7 Article Global Protease Activity Profiling Provides Differential Diagnosis of Pancreatic Cysts. 2017

Ivry, Sam L / Sharib, Jeremy M / Dominguez, Dana A / Roy, Nilotpal / Hatcher, Stacy E / Yip-Schneider, Michele T / Schmidt, C Max / Brand, Randall E / Park, Walter G / Hebrok, Matthias / Kim, Grace E / O'Donoghue, Anthony J / Kirkwood, Kimberly S / Craik, Charles S. ·Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California. · Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, California. · Department of Surgery, University of California, San Francisco, San Francisco, California. · Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California. · Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana. · Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Medicine, Stanford University School of Medicine, Stanford, California. · Department of Pathology, University of California, San Francisco, San Francisco, California. · Skaggs School of Pharmacy and Pharmaceutical Chemistry, University of California, San Diego, La Jolla, California. · Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California. Charles.Craik@ucsf.edu. ·Clin Cancer Res · Pubmed #28424202.

ABSTRACT:

8 Article PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance. 2016

Roy, Nilotpal / Takeuchi, Kenneth K / Ruggeri, Jeanine M / Bailey, Peter / Chang, David / Li, Joey / Leonhardt, Laura / Puri, Sapna / Hoffman, Megan T / Gao, Shan / Halbrook, Christopher J / Song, Yan / Ljungman, Mats / Malik, Shivani / Wright, Christopher V E / Dawson, David W / Biankin, Andrew V / Hebrok, Matthias / Crawford, Howard C. ·Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Wolfson Wohl Cancer Research Center, University of Glasgow, Glasgow G61 1BD, Scotland. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794, USA. · Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Medicine/ Hematology and Oncology, University of California at San Francisco, San Francisco, California 94143, USA. · Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37240, USA. · Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA. ·Genes Dev · Pubmed #28087712.

ABSTRACT: Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

9 Article Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. 2016

Laklai, Hanane / Miroshnikova, Yekaterina A / Pickup, Michael W / Collisson, Eric A / Kim, Grace E / Barrett, Alex S / Hill, Ryan C / Lakins, Johnathon N / Schlaepfer, David D / Mouw, Janna K / LeBleu, Valerie S / Roy, Nilotpal / Novitskiy, Sergey V / Johansen, Julia S / Poli, Valeria / Kalluri, Raghu / Iacobuzio-Donahue, Christine A / Wood, Laura D / Hebrok, Matthias / Hansen, Kirk / Moses, Harold L / Weaver, Valerie M. ·Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA. · Department of Medicine, University of California, San Francisco, San Francisco, California, USA. · Department of Pathology, University of California, San Francisco, San Francisco, California, USA. · Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, Colorado, USA. · Department of Reproductive Medicine, University of California, San Diego Moores Cancer Center, La Jolla, California, USA. · Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. · Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California, USA. · Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. · Department of Oncology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark. · Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy. · Department of Pathology, David Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Gastrointestinal and Liver Pathology Department, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Anatomy, University of California, San Francisco, San Francisco, California, USA. · Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA. · Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA. · Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA. ·Nat Med · Pubmed #27089513.

ABSTRACT: Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.

10 Article p120 Catenin Suppresses Basal Epithelial Cell Extrusion in Invasive Pancreatic Neoplasia. 2016

Hendley, Audrey M / Wang, Yue J / Polireddy, Kishore / Alsina, Janivette / Ahmed, Ishrat / Lafaro, Kelly J / Zhang, Hao / Roy, Nilotpal / Savidge, Samuel G / Cao, Yanna / Hebrok, Matthias / Maitra, Anirban / Reynolds, Albert B / Goggins, Michael / Younes, Mamoun / Iacobuzio-Donahue, Christine A / Leach, Steven D / Bailey, Jennifer M. ·Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. · The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. · Diabetes Center, University of California, San Francisco, San Francisco, California. · Department of Surgery, The University of Texas Health Science Center at Houston, Houston, Texas. · Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston, Houston, Texas. · The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, New York. leachs@mskcc.org Jennifer.M.Bailey@uth.tmc.edu. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas. leachs@mskcc.org Jennifer.M.Bailey@uth.tmc.edu. ·Cancer Res · Pubmed #27032419.

ABSTRACT: Aberrant regulation of cellular extrusion can promote invasion and metastasis. Here, we identify molecular requirements for early cellular invasion using a premalignant mouse model of pancreatic cancer with conditional knockout of p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high-grade pancreatic intraepithelial neoplasia (PanIN) lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes, which is mediated, in part, through NF-κB signaling. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, retain epithelial morphology, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by the activation of S1P/S1pr2 signaling. In the context of oncogenic Kras, p120 catenin loss significantly reduces expression of genes mediating S1P/S1pr2 signaling in vivo and in vitro, and this effect is mediated at least, in part, through activation of NF-κB. These results provide insight into mechanisms controlling early events in the metastatic process and suggest that p120 catenin and S1P/S1pr2 signaling enhance cancer progression by regulating epithelial cell invasion. Cancer Res; 76(11); 3351-63. ©2016 AACR.

11 Article Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation. 2015

Roy, Nilotpal / Malik, Shivani / Villanueva, Karina E / Urano, Atsushi / Lu, Xinyuan / Von Figura, Guido / Seeley, E Scott / Dawson, David W / Collisson, Eric A / Hebrok, Matthias. ·Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA; · Department of Medicine/Hematology and Oncology, University of California at San Francisco, San Francisco, California 94143, USA; · II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar der Technischen Universität München, 81675 Munich, Germany; · Department of Pathology, University of California at San Francisco, San Francisco, California 94143, USA; · Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA. · Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA; mhebrok@diabetes.ucsf.edu. ·Genes Dev · Pubmed #25792600.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a "ductal-like" state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo "ductal retrogression" to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA.

12 Article NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas. 2015

Chen, Nai-Ming / Singh, Garima / Koenig, Alexander / Liou, Geou-Yarh / Storz, Peter / Zhang, Jin-San / Regul, Lisanne / Nagarajan, Sankari / Kühnemuth, Benjamin / Johnsen, Steven A / Hebrok, Matthias / Siveke, Jens / Billadeau, Daniel D / Ellenrieder, Volker / Hessmann, Elisabeth. ·Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany. · Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps-University, Marburg, Germany. · Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota. · Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. · Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota; School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China. · Clinic for General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany. · Diabetes Center, University of California San Francisco, San Francisco, California. · II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität, Munich, Germany. · Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota. · Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany. Electronic address: elisabeth.hessmann@med.uni-goettingen.de. ·Gastroenterology · Pubmed #25623042.

ABSTRACT: BACKGROUND & AIMS: Oncogenic mutations in KRAS contribute to the development of pancreatic ductal adenocarcinoma, but are not sufficient to initiate carcinogenesis. Secondary events, such as inflammation-induced signaling via the epidermal growth factor receptor (EGFR) and expression of the SOX9 gene, are required for tumor formation. Herein we sought to identify the mechanisms that link EGFR signaling with activation of SOX9 during acinar-ductal metaplasia, a transdifferentiation process that precedes pancreatic carcinogenesis. METHODS: We analyzed pancreatic tissues from Kras(G12D);pdx1-Cre and Kras(G12D);NFATc1(Δ/Δ);pdx1-Cre mice after intraperitoneal administration of caerulein, vs cyclosporin A or dimethyl sulfoxide (controls). Induction of EGFR signaling and its effects on the expression of Nuclear factor of activated T cells c1 (NFATc1) or SOX9 were investigated by quantitative reverse-transcription polymerase chain reaction, immunoblot, and immunohistochemical analyses of mouse and human tissues and acinar cell explants. Interactions between NFATc1 and partner proteins and effects on DNA binding or chromatin modifications were studied using co-immunoprecipitation and chromatin immunoprecipitation assays in acinar cell explants and mouse tissue. RESULTS: EGFR activation induced expression of NFATc1 in metaplastic areas from patients with chronic pancreatitis and in pancreatic tissue from Kras(G12D) mice. EGFR signaling also promoted formation of a complex between NFATc1 and C-JUN in dedifferentiating mouse acinar cells, leading to activation of Sox9 transcription and induction of acinar-ductal metaplasia. Pharmacologic inhibition of NFATc1 or disruption of the Nfatc1 gene inhibited EGFR-mediated induction of Sox9 transcription and blocked acinar-ductal transdifferentiation and pancreatic cancer initiation in mice. CONCLUSIONS: EGFR signaling induces expression of NFATc1 and Sox9, leading to acinar cell transdifferentiation and initiation of pancreatic cancer. Strategies designed to disrupt this pathway might be developed to prevent pancreatic cancer initiation in high-risk patients with chronic pancreatitis.

13 Article Antithetical NFATc1-Sox2 and p53-miR200 signaling networks govern pancreatic cancer cell plasticity. 2015

Singh, Shiv K / Chen, Nai-Ming / Hessmann, Elisabeth / Siveke, Jens / Lahmann, Marlen / Singh, Garima / Voelker, Nadine / Vogt, Sophia / Esposito, Irene / Schmidt, Ansgar / Brendel, Cornelia / Stiewe, Thorsten / Gaedcke, Jochen / Mernberger, Marco / Crawford, Howard C / Bamlet, William R / Zhang, Jin-San / Li, Xiao-Kun / Smyrk, Thomas C / Billadeau, Daniel D / Hebrok, Matthias / Neesse, Albrecht / Koenig, Alexander / Ellenrieder, Volker. ·Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg, Germany. · Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany. · II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich, Germany. · Institute for Molecular Tumor Biology, Philipps University, Marburg, Germany. · Institute of Pathology, Helmholtz Zentrum, Munich, Germany. · Institute of Pathology, Philipps University, Marburg, Germany. · Department of Hematology and Oncology, Philipps University, Marburg, Germany. · Department of Surgery, University Medical Center Goettingen, Goettingen, Germany. · Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, FL, USA. · Division of Biostatistics, College of Medicine, Mayo Clinic, Rochester, MN, USA. · Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China. · School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China. · Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA. · Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA. · Diabetes Center, USCF, San Francisco, CA, USA. · Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA. · Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany volker.ellenrieder@med.uni-goettingen.de. ·EMBO J · Pubmed #25586376.

ABSTRACT: In adaptation to oncogenic signals, pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial-mesenchymal transition (EMT), a process combining tumor cell dedifferentiation with acquisition of stemness features. However, the mechanisms linking oncogene-induced signaling pathways with EMT and stemness remain largely elusive. Here, we uncover the inflammation-induced transcription factor NFATc1 as a central regulator of pancreatic cancer cell plasticity. In particular, we show that NFATc1 drives EMT reprogramming and maintains pancreatic cancer cells in a stem cell-like state through Sox2-dependent transcription of EMT and stemness factors. Intriguingly, NFATc1-Sox2 complex-mediated PDAC dedifferentiation and progression is opposed by antithetical p53-miR200c signaling, and inactivation of the tumor suppressor pathway is essential for tumor dedifferentiation and dissemination both in genetically engineered mouse models (GEMM) and human PDAC. Based on these findings, we propose the existence of a hierarchical signaling network regulating PDAC cell plasticity and suggest that the molecular decision between epithelial cell preservation and conversion into a dedifferentiated cancer stem cell-like phenotype depends on opposing levels of p53 and NFATc1 signaling activities.

14 Article Dicer regulates differentiation and viability during mouse pancreatic cancer initiation. 2014

Morris, John P / Greer, Renee / Russ, Holger A / von Figura, Guido / Kim, Grace E / Busch, Anke / Lee, Jonghyeob / Hertel, Klemens J / Kim, Seung / McManus, Michael / Hebrok, Matthias. ·Diabetes Center, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America. · Department of Pathology, University of California San Francisco, San Francisco, California, United States of America. · Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, California, United States of America. · Department of Developmental Biology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States of America. ·PLoS One · Pubmed #24788257.

ABSTRACT: miRNA levels are altered in pancreatic ductal adenocarcinoma (PDA), the most common and lethal pancreatic malignancy, and intact miRNA processing is essential for lineage specification during pancreatic development. However, the role of miRNA processing in PDA has not been explored. Here we study the role of miRNA biogenesis in PDA development by deleting the miRNA processing enzyme Dicer in a PDA mouse model driven by oncogenic Kras. We find that loss of Dicer accelerates Kras driven acinar dedifferentiation and acinar to ductal metaplasia (ADM), a process that has been shown to precede and promote the specification of PDA precursors. However, unconstrained ADM also displays high levels of apoptosis. Dicer loss does not accelerate development of Kras driven PDA precursors or PDA, but surprisingly, we observe that mouse PDA can develop without Dicer, although at the expense of proliferative capacity. Our data suggest that intact miRNA processing is involved in both constraining pro-tumorigenic changes in pancreatic differentiation as well as maintaining viability during PDA initiation.

15 Article The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. 2014

von Figura, Guido / Fukuda, Akihisa / Roy, Nilotpal / Liku, Muluye E / Morris Iv, John P / Kim, Grace E / Russ, Holger A / Firpo, Matthew A / Mulvihill, Sean J / Dawson, David W / Ferrer, Jorge / Mueller, William F / Busch, Anke / Hertel, Klemens J / Hebrok, Matthias. ·1] Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA [2] II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany [3]. · 1] Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA [2] Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan [3]. · 1] Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA [2]. · Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA. · Department of Pathology, University of California, San Francisco, San Francisco, California 94143, USA. · 1] Department of Surgery [2] Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84115, USA. · Department of Pathology, University of California, Los Angeles, California 90095, USA. · Department of Medicine, Imperial College London, W12 ONN London, UK. · Department of Microbiology & Molecular Genetics, University of California, Irvine, California 92697, USA. ·Nat Cell Biol · Pubmed #24561622.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN-PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Although Brg1-null IPMN-PDA develops rapidly, it possesses a distinct transcriptional profile compared with PanIN-PDA driven by mutant Kras and hemizygous p53 deletion. IPMN-PDA also is less lethal, mirroring prognostic trends in PDA patients. In addition, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, this study implicates Brg1 as a determinant of context-dependent Kras-driven pancreatic tumorigenesis and suggests that chromatin remodelling may underlie the development of distinct PDA subsets.

16 Article Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. 2014

von Figura, Guido / Morris, John P / Wright, Christopher V E / Hebrok, Matthias. ·Department of Medicine, Diabetes Center, University of California-San Francisco, , San Francisco, California, USA. ·Gut · Pubmed #23645620.

ABSTRACT: OBJECTIVES: Emerging evidence from mouse models suggests that mutant Kras can drive the development of pancreatic ductal adenocarcinoma (PDA) precursors from acinar cells by enforcing ductal de-differentiation at the expense of acinar identity. Recently, human genome-wide association studies have identified NR5A2, a key regulator of acinar function, as a susceptibility locus for human PDA. We investigated the role of Nr5a2 in exocrine maintenance, regeneration and Kras driven neoplasia. DESIGN: To investigate the function of Nr5a2 in the pancreas, we generated mice with conditional pancreatic Nr5a2 deletion (PdxCre(late); Nr5a2(c/c)). Using this model, we evaluated acinar differentiation, regeneration after caerulein pancreatitis and Kras driven pancreatic neoplasia in the setting of Nr5a2 deletion. RESULTS: We show that Nr5a2 is not required for the development of the pancreatic acinar lineage but is important for maintenance of acinar identity. Nr5a2 deletion leads to destabilisation of the mature acinar differentiation state, acinar to ductal metaplasia and loss of regenerative capacity following acute caerulein pancreatitis. Loss of Nr5a2 also dramatically accelerates the development of oncogenic Kras driven acinar to ductal metaplasia and PDA precursor lesions. CONCLUSIONS: Nr5a2 is a key regulator of acinar plasticity. It is required for maintenance of acinar identity and re-establishing acinar fate during regeneration. Nr5a2 also constrains pancreatic neoplasia driven by oncogenic Kras, providing functional evidence supporting a potential role as a susceptibility gene for human PDA.

17 Article Canonical wnt signaling is required for pancreatic carcinogenesis. 2013

Zhang, Yaqing / Morris, John P / Yan, Wei / Schofield, Heather K / Gurney, Austin / Simeone, Diane M / Millar, Sarah E / Hoey, Timothy / Hebrok, Matthias / Pasca di Magliano, Marina. ·Department of Surgery, University of Michigan Medical School, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA. ·Cancer Res · Pubmed #23761328.

ABSTRACT: Wnt ligand expression and activation of the Wnt/β-catenin pathway have been associated with pancreatic ductal adenocarcinoma, but whether Wnt activity is required for the development of pancreatic cancer has remained unclear. Here, we report the results of three different approaches to inhibit the Wnt/β-catenin pathway in a established transgenic mouse model of pancreatic cancer. First, we found that β-catenin null cells were incapable of undergoing acinar to ductal metaplasia, a process associated with development of premalignant pancreatic intraepithelial neoplasia lesions. Second, we addressed the specific role of ligand-mediated Wnt signaling through inducible expression of Dkk1, an endogenous secreted inhibitor of the canonical Wnt pathway. Finally, we targeted the Wnt pathway with OMP-18R5, a therapeutic antibody that interacts with multiple Frizzled receptors. Together, these approaches showed that ligand-mediated activation of the Wnt/β-catenin pathway is required to initiate pancreatic cancer. Moreover, they establish that Wnt signaling is also critical for progression of pancreatic cancer, a finding with potential therapeutic implications.

18 Article Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer. 2013

Lin, Wan-chi / Rajbhandari, Nirakar / Liu, Chengbao / Sakamoto, Kazuhito / Zhang, Qian / Triplett, Aleata A / Batra, Surinder K / Opavsky, Rene / Felsher, Dean W / DiMaio, Dominick J / Hollingsworth, Michael A / Morris, John P / Hebrok, Matthias / Witkiewicz, Agnieszka K / Brody, Jonathan R / Rui, Hallgeir / Wagner, Kay-Uwe. ·Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE 68198-5950, USA. ·Cancer Res · Pubmed #23467612.

ABSTRACT: The initiation and progression of pancreatic ductal adenocarcinoma (PDAC) is governed by a series of genetic and epigenetic changes, but it is still unknown whether these alterations are required for the maintenance of primary and metastatic PDAC. We show here that the c-Myc oncogene is upregulated throughout the entire process of neoplastic progression in human PDAC and in genetically engineered mice that express mutant Kras. To experimentally address whether c-Myc is essential for the growth and survival of cancer cells, we developed a novel mouse model that allows a temporally and spatially controlled expression of this oncogene in pancreatic progenitors and derived lineages of the exocrine pancreas. Unlike previous reports, upregulation of c-Myc was sufficient to induce the formation of adenocarcinomas after a short latency without additional genetic manipulation of cell survival pathways. Deficiency in Cdkn2a increased the rate of metastasis but had no effect on tumor latency or c-Myc-mediated cancer maintenance. Despite a macroscopically complete regression of primary, metastatic, and transplantable tumors following the ablation of c-Myc, some cancer cells remained dormant. A significant number of these residual neoplastic cells expressed cancer stem cell markers, and re-expression of exogenous c-Myc in these cells led to rapid cancer recurrence. Collectively, the results of this study suggest that c-Myc plays a significant role in the progression and maintenance of PDAC, but besides targeting this oncogene or its downstream effectors, additional therapeutic strategies are necessary to eradicate residual cancer cells to prevent disease recurrence.

19 Article Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. 2012

Kopp, Janel L / von Figura, Guido / Mayes, Erin / Liu, Fen-Fen / Dubois, Claire L / Morris, John P / Pan, Fong Cheng / Akiyama, Haruhiko / Wright, Christopher V E / Jensen, Kristin / Hebrok, Matthias / Sander, Maike. ·Departments of Pediatrics and Cellular and Molecular Medicine, University of California-San Diego, La Jolla, CA 92093-0695, USA. ·Cancer Cell · Pubmed #23201164.

ABSTRACT: Tumors are largely classified by histologic appearance, yet morphologic features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.

20 Article Elevated Hedgehog/Gli signaling causes beta-cell dedifferentiation in mice. 2011

Landsman, Limor / Parent, Audrey / Hebrok, Matthias. ·Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143, USA. ·Proc Natl Acad Sci U S A · Pubmed #21969560.

ABSTRACT: Although Hedgehog (Hh) signaling regulates cell differentiation during pancreas organogenesis, the consequences of pathway up-regulation in adult β-cells in vivo have not been investigated. Here, we elevate Hh signaling in β-cells by expressing an active version of the GLI2 transcription factor, a mediator of the Hh pathway, in β-cells that are also devoid of primary cilia, a critical regulator of Hh activity. We show that increased Hh signaling leads to impaired β-cell function and insulin secretion, resulting in glucose intolerance in transgenic mice. This phenotype was accompanied by reduced expression of both genes critical for β-cell function and transcription factors associated with their mature phenotype. Increased Hh signaling further correlated with increased expression of the precursor cell markers Hes1 and Sox9, both direct Hh targets that are normally excluded from β-cells. Over time, the majority of β-cells down-regulated GLI2 levels, thereby regaining the full differentiation state and restoring normoglycemia in transgenic mice. However, sustained high Hh levels in some insulin-producing cells further eroded the β-cell identity and eventually led to the development of undifferentiated pancreatic tumors. Summarily, our results indicate that deregulation of the Hh pathway impairs β-cell function by interfering with the mature β-cell differentiation state.

21 Article Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. 2011

Fukuda, Akihisa / Wang, Sam C / Morris, John P / Folias, Alexandra E / Liou, Angela / Kim, Grace E / Akira, Shizuo / Boucher, Kenneth M / Firpo, Matthew A / Mulvihill, Sean J / Hebrok, Matthias. ·Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. ·Cancer Cell · Pubmed #21481787.

ABSTRACT: Chronic pancreatitis is a well-known risk factor for pancreatic ductal adenocarcinoma (PDA) development in humans, and inflammation promotes PDA initiation and progression in mouse models of the disease. However, the mechanistic link between inflammatory damage and PDA initiation is unclear. Using a Kras-driven mouse model of PDA, we establish that the inflammatory mediator Stat3 is a critical component of spontaneous and pancreatitis-accelerated PDA precursor formation and supports cell proliferation, metaplasia-associated inflammation, and MMP7 expression during neoplastic development. Furthermore, we show that Stat3 signaling enforces MMP7 expression in PDA cells and that MMP7 deletion limits tumor size and metastasis in mice. Finally, we demonstrate that serum MMP7 level in human patients with PDA correlated with metastatic disease and survival.

22 Article Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. 2010

Morris, John P / Cano, David A / Sekine, Shigeki / Wang, Sam C / Hebrok, Matthias. ·Diabetes Center, Department of Medicine, UCSF, San Francisco, California 94143, USA. ·J Clin Invest · Pubmed #20071774.

ABSTRACT: Cellular plasticity in adult organs is involved in both regeneration and carcinogenesis. WT mouse acinar cells rapidly regenerate following injury that mimics acute pancreatitis, a process characterized by transient reactivation of pathways involved in embryonic pancreatic development. In contrast, such injury promotes the development of pancreatic ductal adenocarcinoma (PDA) precursor lesions in mice expressing a constitutively active form of the GTPase, Kras, in the exocrine pancreas. The molecular environment that mediates acinar regeneration versus the development of PDA precursor lesions is poorly understood. Here, we used genetically engineered mice to demonstrate that mutant Kras promotes acinar-to-ductal metaplasia (ADM) and pancreatic cancer precursor lesion formation by blocking acinar regeneration following acute pancreatitis. Our results indicate that beta-catenin is required for efficient acinar regeneration. In addition, canonical beta-catenin signaling, a pathway known to regulate embryonic acinar development, is activated following acute pancreatitis. This regeneration-associated activation of beta-catenin signaling was not observed during the initiation of Kras-induced acinar-to-ductal reprogramming. Furthermore, stabilized beta-catenin signaling antagonized the ability of Kras to reprogram acini into PDA preneoplastic precursors. Therefore, these results suggest that beta-catenin signaling is a critical determinant of acinar plasticity and that it is inhibited during Kras-induced fate decisions that specify PDA precursors, highlighting the importance of temporal regulation of embryonic signaling pathways in the development of neoplastic cell fates.

23 Unspecified Advances in acute and chronic pancreatitis: from development to inflammation and repair. 2013

Pasca di Magliano, Marina / Forsmark, Christopher / Freedman, Steven / Hebrok, Matthias / Pasricha, Pankaj J / Saluja, Ashok / Stanger, Ben Z / Holt, Jane / Serrano, Jose / James, Stephen P / Rustgi, Anil K. ·Division of Surgical Oncology, Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA. ·Gastroenterology · Pubmed #23159450.

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