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Pancreatic Neoplasms: HELP
Articles by Peter Storz
Based on 24 articles published since 2010
(Why 24 articles?)
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Between 2010 and 2020, Peter Storz wrote the following 24 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Editorial Protein kinase D enzymes: novel kinase targets in pancreatic cancer. 2015

Liou, Geou-Yarh / Storz, Peter. ·a Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ·Expert Rev Gastroenterol Hepatol · Pubmed #26174103.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is characterized by advanced stage desmoplastic tumors with a high prevalence of genetic abnormalities. Occurrence of PDA is linked to activating Kras mutations and aberrant epidermal growth factor receptor signaling, leading to additional activation of wild-type Kras. As Kras is difficult to target, there is a constant need to identify novel targets acting downstream of this molecule in driving the formation or progression of PDA. Recently, it was shown that protein kinase D enzymes not only are increasingly expressed in PDA but also causatively linked to the development and progression of this cancer. They act downstream of both mutant Kras and growth factors and therefore may represent ideal novel targets.

2 Editorial Pancreatic oncogenic signaling cascades converge at Protein Kinase D1. 2015

Liou, Geou-Yarh / Leitges, Michael / Storz, Peter. ·a Department of Cancer Biology ; Mayo Clinic Comprehensive Cancer Center; Mayo Clinic ; Jacksonville , FL USA. ·Cell Cycle · Pubmed #25928263.

ABSTRACT: -- No abstract --

3 Editorial Targeting the alternative NF-κB pathway in pancreatic cancer: a new direction for therapy? 2013

Storz, Peter. · ·Expert Rev Anticancer Ther · Pubmed #23617340.

ABSTRACT: -- No abstract --

4 Review Protein kinase C isoforms in the normal pancreas and in pancreatic disease. 2017

Fleming, Alicia K / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA. Electronic address: storz.peter@mayo.edu. ·Cell Signal · Pubmed #28826907.

ABSTRACT: Protein Kinase C isoforms have been implicated in regulating multiple processes within the healthy pancreas. Moreover, their dysregulation contributes to all aspects of pancreatic disease. In this review, with a focus on acinar, ductal, and islet cells, we highlight the roles and contributions of the different PKC isoforms to normal pancreas function. We also discuss the contribution of PKC enzymes to pancreatic diseases, including insulin resistance and diabetes mellitus, as well as pancreatitis and the development and progression of pancreatic cancer.

5 Review Mitochondrial and Oxidative Stress-Mediated Activation of Protein Kinase D1 and Its Importance in Pancreatic Cancer. 2017

Döppler, Heike / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic , Jacksonville, FL , USA. ·Front Oncol · Pubmed #28361035.

ABSTRACT: Due to alterations in their metabolic activity and decreased mitochondrial efficiency, cancer cells often show increased generation of reactive oxygen species (ROS), but at the same time, to avoid cytotoxic signaling and to facilitate tumorigenic signaling, have mechanism in place that keep ROS in check. This requires signaling molecules that convey increases in oxidative stress to signal to the nucleus to upregulate antioxidant genes. Protein kinase D1 (PKD1), the serine/threonine kinase, is one of these ROS sensors. In this mini-review, we highlight the mechanisms of how PKD1 is activated in response to oxidative stress, so far known downstream effectors, as well as the importance of PKD1-initiated signaling for development and progression of pancreatic cancer.

6 Review Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. 2017

Storz, Peter. ·Department of Cancer Biology, Room 306 Griffin Building, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA. ·Nat Rev Gastroenterol Hepatol · Pubmed #28270694.

ABSTRACT: Acinar cells in the adult pancreas show high plasticity and can undergo transdifferentiation to a progenitor-like cell type with ductal characteristics. This process, termed acinar-to-ductal metaplasia (ADM), is an important feature facilitating pancreas regeneration after injury. Data from animal models show that cells that undergo ADM in response to oncogenic signalling are precursors for pancreatic intraepithelial neoplasia lesions, which can further progress to pancreatic ductal adenocarcinoma (PDAC). As human pancreatic adenocarcinoma is often diagnosed at a stage of metastatic disease, understanding the processes that lead to its initiation is important for the discovery of markers for early detection, as well as options that enable an early intervention. Here, the critical determinants of acinar cell plasticity are discussed, in addition to the intracellular and extracellular signalling events that drive acinar cell metaplasia and their contribution to development of PDAC.

7 Review Targeting reactive oxygen species in development and progression of pancreatic cancer. 2017

Durand, Nisha / Storz, Peter. ·a Department of Cancer Biology , Mayo Clinic , Jacksonville , FL , USA. ·Expert Rev Anticancer Ther · Pubmed #27841037.

ABSTRACT: INTRODUCTION: Pancreatic ductal adenocarcinoma (PDA) is characterized by expression of oncogenic KRas which drives all aspects of tumorigenesis. Oncogenic KRas induces the formation of reactive oxygen species (ROS) which have been implicated in initiation and progression of PDA. To facilitate tumor promoting levels and to avoid oncogene-induced senescence or cytotoxicity, ROS homeostasis in PDA cells is balanced by additional up-regulation of antioxidant systems. Areas covered: We examine the sources of ROS in PDA, the mechanisms by which ROS homeostasis is maintained, and the biological consequences of ROS in PDA. Additionally, we discuss the potential mechanisms for targeting ROS homoeostasis as a point of therapeutic intervention. An extensive review of the relevant literature as it relates to the topic was conducted using PubMed. Expert commentary: Even though oncogenic mutations in the KRAS gene have been detected in over 95% of human pancreatic adenocarcinoma, targeting its gene product, KRas, has been difficult. The dependency of PDA cells on balancing ROS homeostasis could be an angle for new prevention or treatment strategies. These include use of antioxidants to prevent formation or progression of precancerous lesions, or methods to increase ROS in tumor cells to toxic levels.

8 Review Targeting protein kinase C subtypes in pancreatic cancer. 2015

Storz, Peter. ·Department of Cancer Biology, Mayo Clinic, Griffin Building, Room 306, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ·Expert Rev Anticancer Ther · Pubmed #25604078.

ABSTRACT: In preclinical studies, protein kinase C (PKC) enzymes have been implicated in regulating many aspects of pancreatic cancer development and progression. However, clinical Phase I or Phase II trials with compounds targeting classical PKC isoforms were not successful. Recent studies implicate that mainly atypical and novel PKC enzymes regulate oncogenic signaling pathways in pancreatic cancer. Members of these two subgroups converge signaling induced by mutant Kras, growth factors and inflammatory cytokines. Different approaches for the development of inhibitors for atypical PKC and novel PKC have been described; and new compounds include allosteric inhibitors and inhibitors that block ATP binding.

9 Article Pomalidomide-induced changes in the pancreatic tumor microenvironment and potential for therapy. 2019

Storz, Peter. ·Mayo Clinic, Griffin Building, Jacksonville, FL, USA. ·Oncoscience · Pubmed #31608297.

ABSTRACT: -- No abstract --

10 Article Targeting the tumor microenvironment in pancreatic ductal adenocarcinoma. 2019

Pandey, Veethika / Storz, Peter. ·a Department of Cancer Biology , Mayo Clinic , Jacksonville , FL , USA. ·Expert Rev Anticancer Ther · Pubmed #31148495.

ABSTRACT:

11 Article Pomalidomide Alters Pancreatic Macrophage Populations to Generate an Immune-Responsive Environment at Precancerous and Cancerous Lesions. 2019

Bastea, Ligia I / Liou, Geou-Yarh / Pandey, Veethika / Fleming, Alicia K / von Roemeling, Christina A / Doeppler, Heike / Li, Zhimin / Qiu, Yushi / Edenfield, Brandy / Copland, John A / Tun, Han W / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida. · Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia. · The Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota. · Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida. · Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida. storz.peter@mayo.edu. ·Cancer Res · Pubmed #30696657.

ABSTRACT: During development of pancreatic cancer, alternatively activated macrophages contribute to fibrogenesis, pancreatic intraepithelial neoplasia (PanIN) lesion growth, and generation of an immunosuppressive environment. Here, we show that the immunomodulatory agent pomalidomide depletes pancreatic lesion areas of alternatively activated macrophage populations. Pomalidomide treatment resulted in downregulation of interferon regulatory factor 4, a transcription factor for M2 macrophage polarization. Pomalidomide-induced absence of alternatively activated macrophages led to a decrease in fibrosis at PanIN lesions and in syngeneic tumors; this was due to generation of an inflammatory, immune-responsive environment with increased expression of IL1α and presence of activated (IFNγ-positive) CD4

12 Article Glycogen synthase kinase-3β ablation limits pancreatitis-induced acinar-to-ductal metaplasia. 2017

Ding, Li / Liou, Geou-Yarh / Schmitt, Daniel M / Storz, Peter / Zhang, Jin-San / Billadeau, Daniel D. ·Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA. · Actuate Therapeutics, Fort Worth, TX, USA. · Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Sciences, and Center for Precision Medicine, The First Affiliated Hospital, Wenzhou Medical University; Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang, PR China. ·J Pathol · Pubmed #28639695.

ABSTRACT: Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3β promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3β attenuates caerulein-induced ADM formation and PanIN progression in Kras

13 Article The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis. 2017

Liou, Geou-Yarh / Bastea, Ligia / Fleming, Alicia / Döppler, Heike / Edenfield, Brandy H / Dawson, David W / Zhang, Lizhi / Bardeesy, Nabeel / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. · Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. · Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN 55905, USA. · Center for Cancer Research, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, 02115 MA, USA. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: storz.peter@mayo.edu. ·Cell Rep · Pubmed #28514653.

ABSTRACT: The contributions of the innate immune system to the development of pancreatic cancer are still ill defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (acinar-to-ductal metaplasia [ADM]), which then gives rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. Here, we demonstrate the presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively activated macrophages, at ADM/PanIN lesions. We further show that Ym1+ macrophages release factors, such as IL-1ra and CCL2, to drive pancreatic fibrogenesis and tumorigenesis. Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly decreased the accumulation of alternatively activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.

14 Article KRas, ROS and the initiation of pancreatic cancer. 2017

Storz, Peter. ·a Department of Cancer Biology , Mayo Clinic Comprehensive Cancer Center, Mayo Clinic , Jacksonville , FL , USA. ·Small GTPases · Pubmed #27215184.

ABSTRACT: Oncogenic mutations of KRAS are the most frequent driver mutations in pancreatic cancer. Expression of an oncogenic allele of KRAS leads to metabolic changes and altered cellular signaling that both can increase the production of intracellular reactive oxygen species (ROS). Increases in ROS have been shown to drive the formation and progression of pancreatic precancerous lesions by upregulating survival and growth factor signaling. A key issue for precancerous and cancer cells is to keep ROS at levels where they are beneficial for tumor development and progression, but below the threshold that leads to induction of senescence or cell death. In KRas-driven neoplasia aberrantly increased ROS levels are therefore balanced by an upregulation of antioxidant genes.

15 Article The PRKD1 promoter is a target of the KRas-NF-κB pathway in pancreatic cancer. 2016

Döppler, Heike / Panayiotou, Richard / Reid, Elizabeth M / Maimo, Willibroad / Bastea, Ligia / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL 32224, USA. ·Sci Rep · Pubmed #27649783.

ABSTRACT: Increased expression of PRKD1 and its gene product protein kinase D1 (PKD1) are linked to oncogenic signaling in pancreatic ductal adenocarcinoma, but a direct functional relationship to oncogenic KRas has not been established so far. We here describe the PRKD1 gene promoter as a target for oncogenic KRas signaling. We demonstrate that KRas-induced activation of the canonical NF-κB pathway is one mechanism of how PRKD1 expression is increased and identify the binding sites for NF-κB in the PRKD1 promoter. Altogether, these results describe a novel mechanism governing PRKD1 gene expression in PDA and provide a functional link between oncogenic KRas, NF-κB and expression of PRKD1.

16 Article Legumain is activated in macrophages during pancreatitis. 2016

Edgington-Mitchell, Laura E / Wartmann, Thomas / Fleming, Alicia K / Gocheva, Vasilena / van der Linden, Wouter A / Withana, Nimali P / Verdoes, Martijn / Aurelio, Luigi / Edgington-Mitchell, Daniel / Lieu, TinaMarie / Parker, Belinda S / Graham, Bim / Reinheckel, Thomas / Furness, John B / Joyce, Johanna A / Storz, Peter / Halangk, Walter / Bogyo, Matthew / Bunnett, Nigel W. ·Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; Laura.Edgington-Mitchell@monash.edu. · Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany; · Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida; · Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York; · Department of Pathology, Stanford University School of Medicine, Stanford, California; · Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, The Netherlands; · Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; · Laboratory for Turbulence Research in Aerospace and Combustion, Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, Victoria, Australia; · Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia; · Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany; · Department of Anatomy and Neuroscience, University of Melbourne and Florey Institute of Neuroscience and Mental Health, Parkville, Victoria Australia; · Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia; and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia. ·Am J Physiol Gastrointest Liver Physiol · Pubmed #27514475.

ABSTRACT: Pancreatitis is an inflammatory disease of the pancreas characterized by dysregulated activity of digestive enzymes, necrosis, immune infiltration, and pain. Repeated incidence of pancreatitis is an important risk factor for pancreatic cancer. Legumain, a lysosomal cysteine protease, has been linked to inflammatory diseases such as atherosclerosis, stroke, and cancer. Until now, legumain activation has not been studied during pancreatitis. We used a fluorescently quenched activity-based probe to assess legumain activation during caerulein-induced pancreatitis in mice. We detected activated legumain by ex vivo imaging, confocal microscopy, and gel electrophoresis. Compared with healthy controls, legumain activity in the pancreas of caerulein-treated mice was increased in a time-dependent manner. Legumain was localized to CD68(+) macrophages and was not active in pancreatic acinar cells. Using a small-molecule inhibitor of legumain, we found that this protease is not essential for the initiation of pancreatitis. However, it may serve as a biomarker of disease, since patients with chronic pancreatitis show strongly increased legumain expression in macrophages. Moreover, the occurrence of legumain-expressing macrophages in regions of acinar-to-ductal metaplasia suggests that this protease may influence reprogramming events that lead to inflammation-induced pancreatic cancer.

17 Article A bright future for protein kinase D1 as a drug target to prevent or treat pancreatic cancer. 2016

Liou, Geou-Yarh / Storz, Peter / Leitges, Michael. ·Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic , Jacksonville, FL, USA. · The Biotechnology Center of Oslo, University of Oslo , Oslo, Norway. ·Mol Cell Oncol · Pubmed #27308552.

ABSTRACT: Pancreatic ductal adenocarcinoma originates from acinar cells that undergo acinar-to-ductal metaplasia (ADM). ADM is initiated in response to growth factors, inflammation, and oncogene activation and leads to a de-differentiated, duct-like phenotype. Our recent publication demonstrated a transforming growth factor α-Kras(G12D)-protein kinase D1-Notch1 signaling axis driving the induction of ADM and further progression to pancreatic intraepithelial neoplasia. This suggests that protein kinase D1 might be an early marker for tumor development and a potential target for drug development.

18 Article Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions. 2016

Liou, Geou-Yarh / Döppler, Heike / DelGiorno, Kathleen E / Zhang, Lizhi / Leitges, Michael / Crawford, Howard C / Murphy, Michael P / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA. · The Biotechnology Centre of Oslo, University of Oslo, 0349 Oslo, Norway. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. · MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: storz.peter@mayo.edu. ·Cell Rep · Pubmed #26947075.

ABSTRACT: The development of pancreatic cancer requires the acquisition of oncogenic KRas mutations and upregulation of growth factor signaling, but the relationship between these is not well established. Here, we show that mutant KRas alters mitochondrial metabolism in pancreatic acinar cells, resulting in increased generation of mitochondrial reactive oxygen species (mROS). Mitochondrial ROS then drives the dedifferentiation of acinar cells to a duct-like progenitor phenotype and progression to PanIN. This is mediated via the ROS-receptive kinase protein kinase D1 and the transcription factors NF-κB1 and NF-κB2, which upregulate expression of the epidermal growth factor, its ligands, and their sheddase ADAM17. In vivo, interception of KRas-mediated generation of mROS reduced the formation of pre-neoplastic lesions. Hence, our data provide insight into how oncogenic KRas interacts with growth factor signaling to induce the formation of pancreatic cancer.

19 Article The crosstalk between acinar cells with 2015

Storz, Peter. ·Department of Cancer Biology; Mayo Clinic Comprehensive Cancer Center; Mayo Clinic ; Jacksonville, FL, USA. ·Oncoimmunology · Pubmed #26155420.

ABSTRACT: Recent studies on the processes that lead to the development of pancreatic cancer indicate that inflammatory macrophages have key functions in the initiation of pre-neoplastic lesions. Specifically, acquisition of an activating

20 Article Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia. 2015

Liou, Geou-Yarh / Döppler, Heike / Braun, Ursula B / Panayiotou, Richard / Scotti Buzhardt, Michele / Radisky, Derek C / Crawford, Howard C / Fields, Alan P / Murray, Nicole R / Wang, Q Jane / Leitges, Michael / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA. · The Biotechnology Centre of Oslo, University of Oslo, N-0349 Oslo, Norway. · Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. ·Nat Commun · Pubmed #25698580.

ABSTRACT: The transdifferentiation of pancreatic acinar cells to a ductal phenotype (acinar-to-ductal metaplasia, ADM) occurs after injury or inflammation of the pancreas and is a reversible process. However, in the presence of activating Kras mutations or persistent epidermal growth factor receptor (EGF-R) signalling, cells that underwent ADM can progress to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic cancer. In transgenic animal models, ADM and PanINs are initiated by high-affinity ligands for EGF-R or activating Kras mutations, but the underlying signalling mechanisms are not well understood. Here, using a conditional knockout approach, we show that protein kinase D1 (PKD1) is sufficient to drive the reprogramming process to a ductal phenotype and progression to PanINs. Moreover, using 3D explant culture of primary pancreatic acinar cells, we show that PKD1 acts downstream of TGFα and Kras, to mediate formation of ductal structures through activation of the Notch pathway.

21 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.

22 Article Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. 2015

Liou, Geou-Yarh / Döppler, Heike / Necela, Brian / Edenfield, Brandy / Zhang, Lizhi / Dawson, David W / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. · Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. storz.peter@mayo.edu. ·Cancer Discov · Pubmed #25361845.

ABSTRACT: SIGNIFICANCE: We here show that oncogenic KRAS in pancreatic acinar cells upregulates the expression of ICAM-1 to attract macrophages. Hence, our results reveal a direct cooperative mechanism between oncogenic Kras mutations and the inflammatory environment to drive the initiation of pancreatic cancer.

23 Article Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity. 2013

Döppler, Heike / Liou, Geou-Yarh / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida, United States of America. ·PLoS One · Pubmed #23301098.

ABSTRACT: BACKGROUND: Increased levels of NF-κB are hallmarks of pancreatic ductal adenocarcinoma (PDAC) and both classical and alternative NF-κB activation pathways have been implicated. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that activation of the alternative pathway is a source for the high basal NF-κB activity in PDAC cell lines. Increased activity of the p52/RelB NF-κB complex is mediated through stabilization and activation of NF-κB-inducing kinase (NIK). We identify proteasomal downregulation of TNF receptor-associated factor 2 (TRAF2) as a mechanism by which levels of active NIK are increased in PDAC cell lines. Such upregulation of NIK expression and activity levels relays to increased proliferation and anchorage-independent growth, but not migration or survival of PDAC cells. CONCLUSIONS/SIGNIFICANCE: Rapid growth is one characteristic of pancreatic cancer. Our data indicates that the TRAF2/NIK/NF-κB2 pathway regulates PDAC cell tumorigenicity and could be a valuable target for therapy of this cancer.

24 Article EGF receptor is required for KRAS-induced pancreatic tumorigenesis. 2012

Ardito, Christine M / Grüner, Barbara M / Takeuchi, Kenneth K / Lubeseder-Martellato, Clara / Teichmann, Nicole / Mazur, Pawel K / Delgiorno, Kathleen E / Carpenter, Eileen S / Halbrook, Christopher J / Hall, Jason C / Pal, Debjani / Briel, Thomas / Herner, Alexander / Trajkovic-Arsic, Marija / Sipos, Bence / Liou, Geou-Yarh / Storz, Peter / Murray, Nicole R / Threadgill, David W / Sibilia, Maria / Washington, M Kay / Wilson, Carole L / Schmid, Roland M / Raines, Elaine W / Crawford, Howard C / Siveke, Jens T. ·Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA. ·Cancer Cell · Pubmed #22975374.

ABSTRACT: Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.