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Pancreatic Neoplasms: HELP
Articles by David W. Dawson
Based on 54 articles published since 2010
(Why 54 articles?)
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Between 2010 and 2020, D. Dawson wrote the following 54 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial Gemcitabine Activates Natural Killer Cells to Attenuate Pancreatic Cancer Recurrence. 2016

Dawson, David W / Fernandez-Zapico, Martin E. ·Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. Electronic address: DDawson@mednet.ucla.edu. · Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota. ·Gastroenterology · Pubmed #27374366.

ABSTRACT: -- No abstract --

2 Review Leveraging Mechanisms Governing Pancreatic Tumorigenesis To Reduce Pancreatic Cancer Mortality. 2016

Donahue, Timothy R / Dawson, David W. ·Department of Surgery, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA. · Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA. Electronic address: ddawson@mednet.ucla.edu. ·Trends Endocrinol Metab · Pubmed #27461042.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a devastating malignancy with limited and modest clinical treatments. High-throughput technologies and accurate disease models now provide a comprehensive picture of the diverse molecular signaling pathways and cellular processes governing PDA tumorigenesis. Central among these is oncogenic KRAS, a mediator of cellular plasticity, metabolic reprogramming, and inflammatory and paracrine signaling required for tumor development and maintenance. Biological aggressiveness is further conferred by a highly fibrotic and immunosuppressive PDA microenvironment that also acts as a barrier to effective drug delivery. The regulation of these mechanisms and their implications for early cancer detection, chemoprevention and therapy are discussed.

3 Review Epidemiology, risk factors, and the promotion of pancreatic cancer: role of the stellate cell. 2012

Pandol, Stephen / Gukovskaya, Anna / Edderkaoui, Mouad / Dawson, David / Eibl, Guido / Lugea, Aurelia. ·Southern California Research Center for Alcoholic Liver and Pancreatic Diseases, University of California and Department of Veterans Affairs, Los Angeles, California, USA. Stephen.pandol@va.gov ·J Gastroenterol Hepatol · Pubmed #22320930.

ABSTRACT: There are approximately 277,000 new cases of pancreatic cancer and 266,000 deaths from pancreatic cancer annually, indicating a mortality rate of 96% of the cases diagnosed. Because of the ineffectiveness of therapies, a major emphasis needs to be placed on prevention. This paper reviews the epidemiology and risk factors for pancreatic cancer, and uses this information to propose plausible research directions for determining the biological mechanisms mediating the effects of risk factors on the promotion of pancreatic cancer, with a focus on the pancreatic stellate cell.

4 Review Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers. 2012

White, Bryan D / Chien, Andy J / Dawson, David W. ·Science and Technology Program, University of Washington Bothell, Bothell, Washington, USA. bdwhite@u.washington.edu ·Gastroenterology · Pubmed #22155636.

ABSTRACT: Aberrant Wnt/β-catenin signaling is widely implicated in numerous malignancies, including cancers of the gastrointestinal tract. Dysregulation of signaling is traditionally attributed to mutations in Axin, adenomatous polyposis coli, and β-catenin that lead to constitutive hyperactivation of the pathway. However, Wnt/β-catenin signaling is also modulated through various other mechanisms in cancer, including cross talk with other altered signaling pathways. A more complex view of Wnt/β-catenin signaling and its role in gastrointestinal cancers is now emerging as divergent phenotypic outcomes are found to be dictated by temporospatial context and relative levels of pathway activation. This review summarizes the dysregulation of Wnt/β-catenin signaling in colorectal carcinoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, with particular emphasis on the latter two. We conclude by addressing some of the major challenges faced in attempting to target the pathway in the clinic.

5 Clinical Trial Pancreatic cancer patients with lymph node involvement by direct tumor extension have similar survival to those with node-negative disease. 2015

Williams, Jennifer L / Nguyen, Andrew H / Rochefort, Matthew / Muthusamy, V Raman / Wainberg, Zev A / Dawson, David W / Tomlinson, James S / Hines, O Joe / Reber, Howard A / Donahue, Timothy R. ·Department of Surgery, Harbor-UCLA Medical Center, Torrance, California. · Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California. · Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. · Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, California. · Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California. ·J Surg Oncol · Pubmed #26303811.

ABSTRACT: BACKGROUND: Lymph node (LN) involvement is a well-known poor prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC). However, there have been conflicting results on the significance of the mechanism of LN involvement, "direct" tumor invasion versus "metastatic," disease on patient survival. METHODS: Clinicopathologic records from all patients who underwent resection for PDAC from 1990 to 2014 at a single-institution were reviewed. RESULTS: Of the 385 total patients, there was tumor invasion outside of the pancreas in 289 (75.1%) patients. Overall, 239 (62.1%) had node-positive disease: 220 (92.0%) by "metastatic" involvement, 14 (5.9%) by "direct" tumor extension, and five (2.1%) by a mix of "metastatic" and "direct". There were no significant differences in clinicopathologic factors associated with PDAC survival between "metastatic" and "direct" LN patients. The median overall survival for the whole cohort was 31.1 months. Compared to overall survival in patients with LN-negative disease (median 40.7 months), those with LNs involved by "metastatic" spread was significantly shorter (median 25.7 months, P < 0.001), yet "direct" LN extension was similar (median 48.1 months, P = 0.719). CONCLUSIONS: The mechanism of LN involvement affects PDAC prognosis. Patients with LNs involved by direct extension have similar survival to those with node-negative disease.

6 Article Histone deacetylase inhibition is synthetically lethal with arginine deprivation in pancreatic cancers with low argininosuccinate synthetase 1 expression. 2020

Kim, Stephanie S / Xu, Shili / Cui, Jing / Poddar, Soumya / Le, Thuc M / Hayrapetyan, Hovhannes / Li, Luyi / Wu, Nanping / Moore, Alexandra M / Zhou, Lei / Yu, Alice C / Dann, Amanda M / Elliott, Irmina A / Abt, Evan R / Kim, Woosuk / Dawson, David W / Radu, Caius G / Donahue, Timothy R. ·Department of Surgery, UCLA, Los Angeles, CA, 90095, USA. · Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Hubei 430022, China. · Ahmanson Translational Imaging Division, UCLA, Los Angeles, CA, 90095, USA. · Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, 90095, USA. · Department of Pancreatic and Thyroidal Surgery, Shengjing Hospital, China Medical University, Shenyang 110003, China. · Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA 90095, USA. · Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, 90095, USA. · David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA. ·Theranostics · Pubmed #31903153.

ABSTRACT: Arginine (Arg) deprivation is a promising therapeutic approach for tumors with low argininosuccinate synthetase 1 (ASS1) expression. However, its efficacy as a single agent therapy needs to be improved as resistance is frequently observed.

7 Article p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity. 2019

Torres, Carolina / Mancinelli, Georgina / Cordoba-Chacon, Jose / Viswakarma, Navin / Castellanos, Karla / Grimaldo, Sam / Kumar, Sandeep / Principe, Daniel / Dorman, Matthew J / McKinney, Ronald / Hirsch, Emilio / Dawson, David / Munshi, Hidayatullah G / Rana, Ajay / Grippo, Paul J. ·Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL 60612; ctp@ugr.es pgrippo@uic.edu. · Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL 60612. · Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL 60612. · Research, Jesse Brown VA Medical Center, Chicago, IL 60612. · Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612. · Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095. · Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095. · Department of Medicine, Northwestern University, Chicago, IL 60611. ·Proc Natl Acad Sci U S A · Pubmed #31266893.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor survival and resistance to conventional therapies. PI3K signaling is implicated in both disease initiation and progression, and specific inhibitors of selected PI3K p110 isoforms for managing solid tumors are emerging. We demonstrate that increased activation of PI3K signals cooperates with oncogenic Kras to promote aggressive PDAC in vivo. The p110γ isoform is overexpressed in tumor tissue and promotes carcinogenesis via canonical AKT signaling. Its selective blockade sensitizes tumor cells to gemcitabine in vitro, and genetic ablation of p110γ protects against Kras-induced tumorigenesis. Diet/obesity was identified as a crucial means of p110 subunit up-regulation, and in the setting of a high-fat diet, p110γ ablation failed to protect against tumor development, showing increased activation of pAKT and hepatic damage. These observations suggest that a careful and judicious approach should be considered when targeting p110γ for therapy, particularly in obese patients.

8 Article Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming. 2019

Koutsioumpa, Marina / Hatziapostolou, Maria / Polytarchou, Christos / Tolosa, Ezequiel J / Almada, Luciana L / Mahurkar-Joshi, Swapna / Williams, Jennifer / Tirado-Rodriguez, Ana Belen / Huerta-Yepez, Sara / Karavias, Dimitrios / Kourea, Helen / Poultsides, George A / Struhl, Kevin / Dawson, David W / Donahue, Timothy R / Fernández-Zapico, Martín E / Iliopoulos, Dimitrios. ·Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA. · Biological Sciences, University of Southampton, Southampton, UK. · Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK. · Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK. · Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota, USA. · Department of Surgery, Division of General Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA. · Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Mexico City, Mexico. · Department of Pathology, School of Medicine, University of Patras, Patras, Greece. · Department of Surgery, Stanford University School of Medicine, Stanford, California, USA. · Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA. ·Gut · Pubmed #30337373.

ABSTRACT: OBJECTIVE: Despite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis. DESIGN: DNA methylation sequencing and gene expression microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo. RESULTS: We define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. CONCLUSION: Together our findings define a new tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.

9 Article KRAS 2018

Principe, Daniel R / Overgaard, Nana Haahr / Park, Alex J / Diaz, Andrew M / Torres, Carolina / McKinney, Ronald / Dorman, Matthew J / Castellanos, Karla / Schwind, Regina / Dawson, David W / Rana, Ajay / Maker, Ajay / Munshi, Hidayatullah G / Rund, Lauretta A / Grippo, Paul J / Schook, Lawrence B. ·Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL, USA. · Department of Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark Copenhagen, Copenhagen, Denmark. · University of Illinois Department of Animal Sciences, Urbana-Champaign, IL, USA. · Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA. · Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA. · Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. · Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA. · Department of Medicine, Northwestern University, Chicago, IL, USA. · Institute for Genomic Biology, University of Illinois, Urbana-Champaign, IL, USA. · Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA. pgrippo@uic.edu. · University of Illinois Department of Animal Sciences, Urbana-Champaign, IL, USA. schook@illinois.edu. · Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA. schook@illinois.edu. ·Sci Rep · Pubmed #30135483.

ABSTRACT: Although survival has improved in recent years, the prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains poor. Despite substantial differences in anatomy, physiology, genetics, and metabolism, the overwhelming majority of preclinical testing relies on transgenic mice. Hence, while mice have allowed for tremendous advances in cancer biology, they have been a poor predictor of drug performance/toxicity in the clinic. Given the greater similarity of sus scrofa pigs to humans, we engineered transgenic sus scrofa expressing a LSL-KRAS

10 Article Metformin Decreases the Incidence of Pancreatic Ductal Adenocarcinoma Promoted by Diet-induced Obesity in the Conditional KrasG12D Mouse Model. 2018

Chang, Hui-Hua / Moro, Aune / Chou, Caroline Ei Ne / Dawson, David W / French, Samuel / Schmidt, Andrea I / Sinnett-Smith, James / Hao, Fang / Hines, O Joe / Eibl, Guido / Rozengurt, Enrique. ·Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg, Freiburg, Germany. · Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. GEibl@mednet.ucla.edu. ·Sci Rep · Pubmed #29651002.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a particularly deadly disease. Chronic conditions, including obesity and type-2 diabetes are risk factors, thus making PDAC amenable to preventive strategies. We aimed to characterize the chemo-preventive effects of metformin, a widely used anti-diabetic drug, on PDAC development using the Kras

11 Article Thioredoxin system-mediated regulation of mutant Kras associated pancreatic neoplasia and cancer. 2017

Schultz, Michelle A / Diaz, Andrew M / Smite, Sharon / Lay, Anna R / DeCant, Brian / McKinney, Ronald / Mascarinas, Windel E / Xia, Yinglin / Neumann, Carola / Bentrem, David / Dawson, David W / Grippo, Paul J. ·Division of Gastroenterology, Department of Medicine, University of Illinois-Chicago, Chicago IL 60612, USA. · Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago IL 60611, USA. · Department of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA. · Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center, Pittsburgh PA 15232, USA. ·Oncotarget · Pubmed #29190947.

ABSTRACT: Peroxiredoxin-1 (Prdx1), a member of the thioredoxin (Txn) system, is overexpressed and correlates with poor prognosis in pancreatic cancer patients and can suppress Kras signaling through redox-mediated inhibition of ERK and AKT in lung and breast cancer. Its redox function is maintained by Txn and sulfiredoxin (Srxn), and its tumor promoting functions are activated by post-translational modification. We studied the role of the Txn system in pancreatic neoplasia and cancer by determining how it regulates the phosphorylation of Kras effectors and by determining its association with patient survival. We found that elevated Prdx1 nuclear localization significantly correlated with better patient survival. Our data also demonstrate that the expression of the Txn system is dysregulated, with elevated Prdx1 expression and significantly decreased Txn and Srxn expression in pancreatic lesions of targeted mutant Kras mouse models. This correlated with distinct differences in the interconversion of Prdx1 oligomers that affect its ability to regulate ERK and AKT phosphorylation. Our data also suggest that Prdx1 post-translational modification and oligomerization suppress Prdx1 mediated redox regulation of ERK phosphorylation. We observed distinct differences in Txn expression and in the ability of pTyr-Prdx1 to bind to pERK in a PanIN model of pancreatic neoplasia as compared to an IPMN model, indicating a distinct difference in the function of post-translationally modified Prdx1 in cells with less Txn expression. Modified Txn system function and post-translational regulation may therefore play a significant role in pancreatic tumorigenesis by altering Kras effector phosphorylation and inhibiting the tumor suppressive redox functions of Prdx1.

12 Article Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice. 2017

Chang, Hui-Hua / Moro, Aune / Takakura, Kazuki / Su, Hsin-Yuan / Mo, Allen / Nakanishi, Masako / Waldron, Richard T / French, Samuel W / Dawson, David W / Hines, O Joe / Li, Gang / Go, Vay Liang W / Sinnett-Smith, James / Pandol, Stephen J / Lugea, Aurelia / Gukovskaya, Anna S / Duff, Michael O / Rosenberg, Daniel W / Rozengurt, Enrique / Eibl, Guido. ·Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America. · Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America. · Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States of America. · Pancreatic Research Group, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America. · Center for Molecular Oncology, UCONN Health, Farmington, CT, United States of America. · Department of Pathology, Harbor-UCLA Medical Center, Torrance, CA, United States of America. · Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America. · Department of Biostatistics, School of Public Health at UCLA, Los Angeles, CA, United States of America. · Department of Genetics and Genome Sciences, UCONN Health, Farmington, CT, United States of America. ·PLoS One · Pubmed #28886117.

ABSTRACT: Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet-induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer.

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 Direct growth-inhibitory effects of prostaglandin E2 in pancreatic cancer cells in vitro through an EP4/PKA-mediated mechanism. 2017

Schmidt, Andrea / Sinnett-Smith, James / Young, Steven / Chang, Hui-Hua / Hines, O Joe / Dawson, David W / Rozengurt, Enrique / Eibl, Guido. ·Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA; Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg, Freiburg, Germany. · Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA. · Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA. · Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA. Electronic address: GEibl@mednet.ucla.edu. ·Surgery · Pubmed #28222855.

ABSTRACT: BACKGROUND: There is strong evidence linking inflammation and the development of pancreatic ductal adenocarcinoma. Cyclooxygenase-2 (COX-2) and COX-2-derived PGE METHODS: Human pancreatic ductal adenocarcinoma cell lines, Panc-1 and MIA PaCa-2, were treated with PGE RESULTS: PGE CONCLUSION: Our study provides evidence that PGE

15 Article Histone deacetylase inhibitors provoke a tumor supportive phenotype in pancreatic cancer associated fibroblasts. 2017

Nguyen, Andrew H / Elliott, Irmina A / Wu, Nanping / Matsumura, Cynthia / Vogelauer, Maria / Attar, Narsis / Dann, Amanda / Ghukasyan, Razmik / Toste, Paul A / Patel, Sanjeet G / Williams, Jennifer L / Li, Luyi / Dawson, David W / Radu, Caius / Kurdistani, Siavash K / Donahue, Timothy R. ·Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. · Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. · Department of Surgery, Harbor-UCLA Medical Center, Torrance, California, USA. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. · Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. ·Oncotarget · Pubmed #27894105.

ABSTRACT: Although histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs, thus far, they have been unsuccessful in early phase clinical trials for pancreatic ductal adenocarcinoma (PDAC). One potential reason for their poor efficacy is the tumor stroma, where cancer-associated fibroblasts (CAFs) are a prominent cell type and a source of resistance to cancer therapies. Here, we demonstrate that stromal fibroblasts contribute to the poor efficacy of HDACi's in PDAC. HDACi-treated fibroblasts show increased biological aggressiveness and are characterized by increased secretion of pro-inflammatory tumor-supportive cytokines and chemokines. We find that HDAC2 binds to the enhancer and promoter regions of pro-inflammatory genes specifically in CAFs and in silico analysis identified AP-1 to be the most frequently associated transcription factor bound in these regions. Pharmacologic inhibition of pathways upstream of AP-1 suppresses the HDACi-induced inflammatory gene expression and tumor-supportive responses in fibroblasts. Our findings demonstrate that the combination of HDACi's with chemical inhibitors of the AP-1 signaling pathway attenuate the inflammatory phenotype of fibroblasts and may improve the efficacy of HDACi in PDAC and, potentially, in other solid tumors rich in stroma.

16 Article Assessment of a Revised Management Strategy for Patients With Intraductal Papillary Mucinous Neoplasms Involving the Main Pancreatic Duct. 2017

Sugimoto, Motokazu / Elliott, Irmina A / Nguyen, Andrew H / Kim, Stephen / Muthusamy, V Raman / Watson, Rabindra / Hines, O Joe / Dawson, David W / Reber, Howard A / Donahue, Timothy R. ·Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles (UCLA). · Division of Digestive Diseases, David Geffen School of Medicine at UCLA. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA. ·JAMA Surg · Pubmed #27829085.

ABSTRACT: Importance: According to the 2012 International Consensus Guidelines, the diagnostic criterion of intraductal papillary mucinous neoplasms (IPMNs) involving the main duct (MD IPMNs) or the main and branch ducts (mixed IPMNs) of the pancreatic system is a main pancreatic duct (MPD) diameter of 5.0 mm or greater on computed tomography (CT) or magnetic resonance imaging (MRI). However, surgical resection is recommended for patients with an MPD diameter of 10.0 mm or greater, which is characterized as a high-risk stigma. An MPD diameter of 5.0 to 9.0 mm is not an indication for immediate resection. Objectives: To determine an appropriate cutoff (ie, one with high sensitivity and negative predictive value) of the MPD diameter on CT or MRI as a prognostic factor for malignant disease and to propose a new management algorithm for patients with MD or mixed IPMNs. Design, Setting, and Participants: This retrospective cohort study included 103 patients who underwent surgical resection for a preoperative diagnosis of MD or mixed IPMN and in whom IPMN was confirmed by surgical pathologic findings at a single institution from July 1, 1996, to December 31, 2015. Main Outcomes and Measures: Malignant disease was defined as high-grade dysplasia or invasive adenocarcinoma on results of surgical pathologic evaluation. An appropriate MPD diameter on preoperative CT or MRI to predict malignant disease was determined using a receiver operating characteristic curve analysis. The prognostic value of the new management algorithm that incorporated the new MPD diameter cutoff was evaluated. Results: Among the 103 patients undergoing resection for an MD or mixed IPMN (59 men [57.3%]; 44 women [42.7%]; median [range] age, 71 [48-86] years), 64 (62.1%) had malignant disease. Diagnostic accuracy for malignant neoplasms was highest at an MPD diameter cutoff of 7.2 mm (area under the receiver operating characteristic curve, 0.70; 95% CI, 0.59-0.81). An MPD diameter of 7.2 mm or greater was also an independent prognostic factor for malignant neoplasms (odds ratio, 12.76; 95% CI, 2.43-66.88; P = .003) on logistic regression analysis after controlling for preoperative variables. The new management algorithm, which included an MPD diameter of 7.2 mm or greater as one of the high-risk stigmata, had a higher sensitivity (100%), negative predictive value (100%), and accuracy (66%) for malignant disease than the 2012 version of the International Consensus Guidelines (95%, 57%, and 63%, respectively). Conclusions and Relevance: In this single-center, retrospective analysis, an MPD diameter of 7.2 mm was identified as an optimal cutoff for a prognostic factor for malignant disease in MD or mixed IPMN. These data support lowering the accepted criteria for MPD diameter when selecting patients for resection vs surveillance so as not to overlook cancer in IPMN.

17 Article Association of Histopathologic Phenotype of Periampullary Adenocarcinomas With Survival. 2017

Williams, Jennifer L / Chan, Carmen K / Toste, Paul A / Elliott, Irmina A / Vasquez, Charles R / Sunjaya, Dharma B / Swanson, Eric A / Koo, Jamie / Hines, O Joe / Reber, Howard A / Dawson, David W / Donahue, Timothy R. ·Department of Surgery, Harbor-UCLA Medical Center, Los Angeles, California2Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles. · Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles. · Department of Pathology, University of Utah, Salt Lake City. · Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles. · Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles6Department of Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles. ·JAMA Surg · Pubmed #27732711.

ABSTRACT: Importance: Patients with periampullary adenocarcinomas have widely variable survival. These cancers are traditionally categorized by their anatomic location of origin, namely, the duodenum, ampulla, distal common bile duct (CBD), or head of the pancreas. However, they can be alternatively subdivided histopathologically into intestinal or pancreaticobiliary (PB) types, which may more accurately estimate prognosis. Objectives: To identify factors associated with survival in patients with periampullary adenocarcinomas and to compare survival between those having intestinal-type or PB-type cancers originating from the duodenum, ampulla, or distal CBD with those having pancreatic ductal adenocarcinoma (PDAC). Design, Setting, and Participants: This study was a retrospective analysis of medical records in a prospectively maintained database. Three pathologists separately evaluated histopathologic phenotypes at a university-based tertiary referral center. Study participants were all patients (N = 510) who underwent pancreatoduodenectomy for adenocarcinoma between January 1995 and December 2014. Main Outcome and Measure: Overall survival. Results: This study identified 510 patients (mean [SD] age, 66.1 [10.9] years; 245 female [48%]) who underwent pancreatoduodenectomy for adenocarcinomas: 13 duodenal, 110 ampullary, 43 distal CBD, and 344 PDAC. The median overall survival was 61.2 (interquartile range [IQR], 22.0-111.0), 70.4 (IQR, 26.7-147.7), 40.6 (IQR, 15.2-59.6), and 31.4 (IQR, 17.3-86.3) months for patients with cancers of the duodenum, ampulla, distal CBD, or pancreas, respectively (P = .01), indicating a significant difference between the 4 tumor anatomic locations. Most duodenal (61.5% [8 of 13]) and ampullary (51.8% [57 of 110]) cancers were intestinal type, and most distal CBD tumors were PB type (86.0% [37 of 43]). Those with intestinal-type duodenal, ampullary, or distal CBD adenocarcinomas had longer median overall survival than those with PB type (71.7 vs 33.3 months, P = .02) or PDAC (31.4 months, P = .003). There was no survival difference between PB-type cancers and PDAC (33.3 vs 31.4 months, P = .66). On multivariable analysis, histologic grade (hazard ratio [HR], 1.98; 95% CI, 1.56-2.52; P < .001), histopathologic phenotype (HR, 1.75; 95% CI, 1.16-2.64; P = .008), and nodal status (HR, 1.45; 95% CI, 1.12-1.87; P = .05) were significantly associated with survival, while anatomic location was not. Conclusions and Relevance: Histopathologic phenotype is a better prognosticator of survival in patients with periampullary adenocarcinomas than tumor anatomic location. Those with PB-type duodenal, ampullary, or distal CBD adenocarcinomas have survival similar to those with PDAC.

18 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.

19 Article Plectin-1 as a Biomarker of Malignant Progression in Intraductal Papillary Mucinous Neoplasms: A Multicenter Study. 2016

Moris, Maria / Dawson, David W / Jiang, Jennifer / Lewis, Jason / Nassar, Aziza / Takeuchi, Kenneth K / Lay, Anna R / Zhai, Qihui / Donahue, Timothy R / Kelly, Kimberly A / Crawford, Howard C / Wallace, Michael. ·From the *Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL; †Department of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA; Departments of ‡Pathology and Laboratory Medicine, and §Cancer Biology, Mayo Clinic, Jacksonville, FL; ∥Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA; and ¶Department of Bioengineering, School of Engineering and Applied Sciences, and #Robert M. Berne Cardiovasuclar Research Center, School of Medicine, University of Virginia, Charlottesville, VA. ·Pancreas · Pubmed #27101571.

ABSTRACT: OBJECTIVE: This study aimed to evaluate Plectin-1 expression as a biomarker of malignant risk for intraductal papillary mucinous neoplasms (IPMNs). METHODS: Plectin-1 immunohistochemistry (IHC) was performed retrospectively on surgical (n = 71) and cytological (n = 33) specimens from Mayo Clinic Jacksonville and UCLA Medical Center, including IPMNs with low-grade dysplasia, high-grade dysplasia (HGD), or an associated invasive adenocarcinoma. RESULTS: Plectin-1 expression was increased in invasive adenocarcinoma compared with adjacent in situ IPMN (P = 0.005), as well as the in situ HGD component of IPMNs with invasive cancer compared with HGD of IPMNs without invasive cancer (P = 0.02). Plectin IHC discriminated IPMNs with invasive adenocarcinoma from noninvasive IPMN (area under the curve [AUC] of 0.79, 75% sensitivity, and 85% specificity) but was insufficient for discriminating HGD IPMN from low-grade dysplasia IPMNs in surgical resections (AUC of 0.67, 56% sensitivity, and 64% specificity) or fine-needle aspiration specimens (AUC of 0.45). CONCLUSIONS: Although Plectin-1 IHC has insufficient accuracy to be used as a definitive biomarker for malignant risk in the evaluation of IPMN biopsy or cytological specimens, increased Plectin-1 expression observed in both invasive cancer and in situ HGD of malignant IPMNs suggests that it might be successfully leveraged as a cyst fluid biomarker or molecular imaging target.

20 Article TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis. 2016

Principe, Daniel R / DeCant, Brian / Mascariñas, Emman / Wayne, Elizabeth A / Diaz, Andrew M / Akagi, Naomi / Hwang, Rosa / Pasche, Boris / Dawson, David W / Fang, Deyu / Bentrem, David J / Munshi, Hidayatullah G / Jung, Barbara / Grippo, Paul J. ·University of Illinois College of Medicine, Urbana-Champaign, Illinois. · Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. · Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. · Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Comprehensive Cancer Center of Wake Forest University, Winston-Salem, North Carolina. · Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California. · Department of Pathology, Northwestern University, Chicago, Illinois. · Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. · Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Department of Medicine, Northwestern University, Chicago, Illinois. · Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. pgrippo@uic.edu bjung@uic.edu. ·Cancer Res · Pubmed #26980767.

ABSTRACT: In early pancreatic carcinogenesis, TGFβ acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGFβ appears to promote tumor progression. Therefore, to better understand the contributions of TGFβ signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGFβ signals facilitated pancreatic tumorigenesis, whereas global loss of TGFβ signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGFβ1 production, and the resultant restoration of antitumor immune function. Similarly, TGFBR-deficient T cells resisted TGFβ-induced inactivation ex vivo, and adoptive transfer of TGFBR-deficient CD8(+) T cells led to enhanced infiltration and granzyme B-mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGFβ expression correlated with increased fibrosis and associated negatively with expression of granzyme B. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGFβ may promote pancreatic cancer development by affecting stromal and hematopoietic cell function. Therefore, the use of TGFBR inhibition to target components of the tumor microenvironment warrants consideration as a potential therapy for pancreatic cancer, particularly in patients who have already lost tumor-suppressive TGFβ signals in the epithelium. Cancer Res; 76(9); 2525-39. ©2016 AACR.

21 Article Chemotherapy-Induced Inflammatory Gene Signature and Protumorigenic Phenotype in Pancreatic CAFs via Stress-Associated MAPK. 2016

Toste, Paul A / Nguyen, Andrew H / Kadera, Brian E / Duong, Mindy / Wu, Nanping / Gawlas, Irmina / Tran, Linh M / Bikhchandani, Mihir / Li, Luyi / Patel, Sanjeet G / Dawson, David W / Donahue, Timothy R. ·Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. · Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. · Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. tdonahue@mednet.ucla.edu. ·Mol Cancer Res · Pubmed #26979711.

ABSTRACT: IMPLICATIONS: Chemotherapy treatment of pancreatic cancer-associated fibroblasts results in a proinflammatory response driven by stress-associated MAPK signaling that enhances tumor cell growth and invasiveness. Mol Cancer Res; 14(5); 437-47. ©2016 AACR.

22 Article Long-term survival in patients with pancreatic ductal adenocarcinoma. 2016

Stark, Alexander P / Sacks, Greg D / Rochefort, Matthew M / Donahue, Timothy R / Reber, Howard A / Tomlinson, James S / Dawson, David W / Eibl, Guido / Hines, O Joe. ·Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA. · Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA; Department of Surgery, Greater Los Angeles VA Healthcare System, Los Angeles, CA. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA. · Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA. Electronic address: joehines@mednet.ucla.edu. ·Surgery · Pubmed #26847803.

ABSTRACT: BACKGROUND: Long-term survival (LTS) is uncommon for patients with pancreatic ductal adenocarcinoma (PDAC). We sought to identify factors that predict 10-year, LTS after resection of PDAC. METHODS: We identified all patients with PDAC who underwent resection at UCLA after 1990 and included all patients eligible for observed LTS (1/1/1990-12/31/2004). An independent pathologist reconfirmed the diagnosis of PDAC in patients with LTS. Logistic regression was used to predict LTS on the basis of patient and tumor characteristics. RESULTS: Of 173 included patients, 53% were male, median age at diagnosis was 66 years, and median survival was 23 months. The rate of observed LTS was 12.1% (n = 21). Age, sex, number of lymph nodes evaluated, margin status, lymphovascular invasion, and adjuvant chemotherapy and radiation were not associated with LTS. The following were associated with LTS on bivariate analysis: low AJCC stage (Ia, Ib, IIa) (P = .034), negative lymph node status (P = .034), low grade (well-, moderately-differentiated) (P = .001), and absence of perineural invasion (P = .019). Only low grade (odds ratio 7.17, P = .012) and absent perineural invasion (odds ratio 3.28, P = .036) were independently associated with increased odds of LTS. Our multivariate model demonstrated good discriminatory power for LTS, as indicated by a c-statistic of 0.7856. CONCLUSION: Absence of perineural invasion and low tumor grade were associated with greater likelihood of LTS. Understanding the tumor biology of LTS may provide critical insight into a disease that is typically marked by aggressive behavior and limited survival.

23 Article Robust Early Inflammation of the Peripancreatic Visceral Adipose Tissue During Diet-Induced Obesity in the KrasG12D Model of Pancreatic Cancer. 2016

Hertzer, Kathleen M / Xu, Mu / Moro, Aune / Dawson, David W / Du, Lin / Li, Gang / Chang, Hui-Hua / Stark, Alexander P / Jung, Xiaoman / Hines, Oscar Joe / Eibl, Guido. ·From the Departments of *Surgery and †Pathology and Laboratory Medicine,David Geffen School of Medicine at UCLA, Los Angeles, CA; and ‡Department of Biostatistics, Fielding School of Public Health at UCLA, Los Angeles, CA. ·Pancreas · Pubmed #26495779.

ABSTRACT: OBJECTIVES: Obesity increases the incidence of multiple types of cancer. Our previous work has shown that a high-fat, high-calorie diet (HFCD) leads to visceral obesity, pancreatic inflammation, and accelerated pancreatic neoplasia in KrasG12D (KC) mice. In this study, we aimed to investigate the effects of an HFCD on visceral adipose inflammation with emphasis on potential differences between distinct visceral adipose depots. METHODS: We examined the weight and visceral obesity in both wild-type and KC mice on either control diet (CD) or HFCD. After 3 months, mice were killed for histological examination. Multiplex assays were also performed to obtain cytokine profiles between different adipose depots. RESULTS: Both wild-type and KC mice on an HFCD exhibited significantly increased inflammation in the visceral adipose tissue, particularly in the peripancreatic fat (PPF), compared with animals on a CD. This was associated with significantly increased inflammation in the pancreas. Cytokine profiles were different between visceral adipose depots and between mice on the HFCD and CD. CONCLUSIONS: Our results clearly demonstrate that an HFCD leads to obesity and inflammation in the visceral adipose tissue, particularly the PPF. These data suggest that obesity-associated inflammation in PPF may accelerate pancreatic neoplasia in KC mice.

24 Article Calcipotriol Targets LRP6 to Inhibit Wnt Signaling in Pancreatic Cancer. 2015

Arensman, Michael D / Nguyen, Phillip / Kershaw, Kathleen M / Lay, Anna R / Ostertag-Hill, Claire A / Sherman, Mara H / Downes, Michael / Liddle, Christopher / Evans, Ronald M / Dawson, David W. ·Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. · Gene Expression Laboratory, Salk Institute, La Jolla, California. · The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia. · Gene Expression Laboratory, Salk Institute, La Jolla, California. Howard Hughes Medical Institute, Salk Institute, La Jolla, California. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California. ddawson@mednet.ucla.edu. ·Mol Cancer Res · Pubmed #26224368.

ABSTRACT: IMPLICATIONS: This study provides a novel biochemical target through which vitamin D signaling exerts inhibitory effects on Wnt/β-catenin signaling, as well as potential biomarkers for predicting and following tumor response to vitamin D-based therapy.

25 Article Pancreatic cancer patient survival correlates with DNA methylation of pancreas development genes. 2015

Thompson, Michael J / Rubbi, Liudmilla / Dawson, David W / Donahue, Timothy R / Pellegrini, Matteo. ·Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California, 90095, United States of America. · Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, 90095, United States of America; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California, 90095, United States of America. · Department of Surgery, University of California Los Angeles, Los Angeles, California, 90095, United States of America; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, 90095, United States of America; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California, 90095, United States of America. ·PLoS One · Pubmed #26039411.

ABSTRACT: DNA methylation is an epigenetic mark associated with regulation of transcription and genome structure. These markers have been investigated in a variety of cancer settings for their utility in differentiating normal tissue from tumor tissue. Here, we examine the direct correlation between DNA methylation and patient survival. We find that changes in the DNA methylation of key pancreatic developmental genes are strongly associated with patient survival.

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