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Pancreatic Neoplasms: HELP
Articles by Howard C. Crawford
Based on 28 articles published since 2009
(Why 28 articles?)
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Between 2009 and 2019, H. Crawford wrote the following 28 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Somatostatin receptor subtype 2 as pancreatic tumorigenesis suppressor: identification of a new targetable signaling node. 2015

Crawford, Howard C. ·Departments of Molecular & Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, Michigan. Electronic address: howcraw@umich.edu. ·Gastroenterology · Pubmed #25921374.

ABSTRACT: -- No abstract --

2 Editorial KRAS above and beyond - EGFR in pancreatic cancer. 2012

Siveke, Jens T / Crawford, Howard C. · ·Oncotarget · Pubmed #23174662.

ABSTRACT: -- No abstract --

3 Review Signaling Networks That Control Cellular Plasticity in Pancreatic Tumorigenesis, Progression, and Metastasis. 2019

Crawford, Howard C / Pasca di Magliano, Marina / Banerjee, Sulagna. ·Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan. · Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Surgery, University of Michigan, Ann Arbor, Michigan. · Department of Surgery, University of Miami School of Medicine, Miami, Florida; Sylvester Cancer Center, University of Miami, Miami, Florida. Electronic address: Sulagna.Banerjee@med.miami.edu. ·Gastroenterology · Pubmed #30716326.

ABSTRACT: Pancreatic ductal adenocarcinoma is one of the deadliest cancers, and its incidence on the rise. The major challenges in overcoming the poor prognosis with this disease include late detection and the aggressive biology of the disease. Intratumoral heterogeneity; presence of a robust, reactive, and desmoplastic stroma; and the crosstalk between the different tumor components require complete understanding of the pancreatic tumor biology to better understand the therapeutic challenges posed by this disease. In this review, we discuss the processes involved during tumorigenesis encompassing the inherent plasticity of the transformed cells, development of tumor stroma crosstalk, and enrichment of cancer stem cell population during tumorigenesis.

4 Review The secret origins and surprising fates of pancreas tumors. 2014

Bailey, Jennifer M / DelGiorno, Kathleen E / Crawford, Howard C. ·Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, Department of Medicine, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA and Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA. · Department of Medicine, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA and. · Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA crawford.howard@mayo.edu. ·Carcinogenesis · Pubmed #24583923.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is especially deadly due to its recalcitrance to current therapies. One of the unique qualities of PDA that may contribute to this resistance is a striking plasticity of differentiation states starting at tumor formation and continuing throughout tumor progression, including metastasis. Here, we explore the earliest steps of tumor formation and neoplastic progression and how this results in a fascinating cellular heterogeneity that is probably critical for tumor survival and progression. We hypothesize that reinforcing differentiation pathways run awry or targeting morphologically and molecularly distinct tumor stem-like cells may hold promise for future treatments of this deadly disease.

5 Article Hiding in plain sight. 2019

Halbrook, Christopher J / Crawford, Howard C. ·Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. howcraw@med.umich.edu. · Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. · The Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. ·Science · Pubmed #31221844.

ABSTRACT: -- No abstract --

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

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

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

7 Article The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male Mice. 2019

Young, Claire C / Baker, Ryan M / Howlett, Christopher J / Hryciw, Todd / Herman, Joshua E / Higgs, Douglas / Gibbons, Richard / Crawford, Howard / Brown, Arthur / Pin, Christopher L. ·Department of Paediatrics, University of Western Ontario, London, Ontario, Canada; Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; Department of Oncology, University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute, London, Ontario, Canada. · Department of Paediatrics, University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute, London, Ontario, Canada. · Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada. · Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada; Robarts Research Institute, London, Ontario, Canada. · Robarts Research Institute, London, Ontario, Canada. · MRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom. · Molecular & Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, Michigan. · Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada; Robarts Research Institute, London, Ontario, Canada; Children's Health Research Institute, London, Ontario, Canada. · Department of Paediatrics, University of Western Ontario, London, Ontario, Canada; Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; Department of Oncology, University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute, London, Ontario, Canada. Electronic address: cpin@uwo.ca. ·Cell Mol Gastroenterol Hepatol · Pubmed #30510993.

ABSTRACT: Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in North America, accounting for >30,000 deaths annually. Although somatic activating mutations in Methods: Mice allowing conditional loss of Results: Mice lacking Conclusions: Our results indicate the absence of ATRX increases sensitivity to injury and oncogenic KRAS only in female mice. This is an instance of a sex-specific mutation that enhances oncogenic KRAS's ability to promote pancreatic intraepithelial lesion formation.

8 Article STAT3 is a master regulator of epithelial identity and KRAS-driven tumorigenesis. 2018

D'Amico, Stephen / Shi, Jiaqi / Martin, Benjamin L / Crawford, Howard C / Petrenko, Oleksi / Reich, Nancy C. ·Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA. · Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794, USA. · Department of Molecular and Integrative Physiology, Ann Arbor, Michigan 48109, USA. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. ·Genes Dev · Pubmed #30135074.

ABSTRACT: A dichotomy exists regarding the role of signal transducer and activator of transcription 3 (STAT3) in cancer. Functional and genetic studies demonstrate either an intrinsic requirement for STAT3 or a suppressive effect on common types of cancer. These contrasting actions of STAT3 imply context dependency. To examine mechanisms that underlie STAT3 function in cancer, we evaluated the impact of STAT3 activity in KRAS-driven lung and pancreatic cancer. Our study defines a fundamental and previously unrecognized function of STAT3 in the maintenance of epithelial cell identity and differentiation. Loss of STAT3 preferentially associates with the acquisition of mesenchymal-like phenotypes and more aggressive tumor behavior. In contrast, persistent STAT3 activation through Tyr705 phosphorylation confers a differentiated epithelial morphology that impacts tumorigenic potential. Our results imply a mechanism in which quantitative differences of STAT3 Tyr705 phosphorylation, as compared with other activation modes, direct discrete outcomes in tumor progression.

9 Article HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties. 2018

Abel, Ethan V / Goto, Masashi / Magnuson, Brian / Abraham, Saji / Ramanathan, Nikita / Hotaling, Emily / Alaniz, Anthony A / Kumar-Sinha, Chandan / Dziubinski, Michele L / Urs, Sumithra / Wang, Lidong / Shi, Jiaqi / Waghray, Meghna / Ljungman, Mats / Crawford, Howard C / Simeone, Diane M. ·Department of Molecular and Integrative Physiology, University of Michigan Health System, Ann Arbor, United States. · Translational Oncology Program, University of Michigan Health System, Ann Arbor, United States. · Department of Biostatistics, School of Public Health, University of Michigan Health System, Ann Arbor, United States. · Department of Pathology, University of Michigan Health System, Ann Arbor, United States. · Department of Surgery, New York University Langone Health, New York, United States. · Perlmutter Cancer Center, New York University Langone Health, New York, United states. · Department of Radiation Oncology, University of Michigan Health System, Ann Arbor, United States. · Department of Pathology, New York University Langone Health, New York, United States. ·Elife · Pubmed #30074477.

ABSTRACT: The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a human PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, decreased PCSC marker expression, and downregulation of

10 Article MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance. 2017

Farrell, Amy S / Joly, Meghan Morrison / Allen-Petersen, Brittany L / Worth, Patrick J / Lanciault, Christian / Sauer, David / Link, Jason / Pelz, Carl / Heiser, Laura M / Morton, Jennifer P / Muthalagu, Nathiya / Hoffman, Megan T / Manning, Sara L / Pratt, Erica D / Kendsersky, Nicholas D / Egbukichi, Nkolika / Amery, Taylor S / Thoma, Mary C / Jenny, Zina P / Rhim, Andrew D / Murphy, Daniel J / Sansom, Owen J / Crawford, Howard C / Sheppard, Brett C / Sears, Rosalie C. ·Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. · Department of Surgery, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. · Department of Pathology, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. · Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 S.W Sam Jackson Park Road, Portland, OR, 97239, USA. · Computational Biology, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. · Department of Biomedical Engineering and OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. · Cancer Research UK, Beatson Institute, Switchback Road, Bearsden, Glasgow, G61 1BD, UK. · Department of Molecular and Integrative Physiology, University of Michigan, 7744 MS II, 1137 E. Catherine St., Ann Arbor, MI, 48109, USA. · Department of Gastroenterology, Hepatology and Nutrition and Zayed Center for Pancreatic Cancer Research, University of Texas M.D. Anderson Cancer Center, Unit 1466, 1515 Holcombe Blvd, Houston, TX, 77030, USA. · Institute of Cancer Sciences, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK. · Knight Cancer Institute, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. · Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. searsr@ohsu.edu. · Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 S.W Sam Jackson Park Road, Portland, OR, 97239, USA. searsr@ohsu.edu. · Knight Cancer Institute, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. searsr@ohsu.edu. ·Nat Commun · Pubmed #29170413.

ABSTRACT: Intratumoral phenotypic heterogeneity has been described in many tumor types, where it can contribute to drug resistance and disease recurrence. We analyzed ductal and neuroendocrine markers in pancreatic ductal adenocarcinoma, revealing heterogeneous expression of the neuroendocrine marker Synaptophysin within ductal lesions. Higher percentages of Cytokeratin-Synaptophysin dual positive tumor cells correlate with shortened disease-free survival. We observe similar lineage marker heterogeneity in mouse models of pancreatic ductal adenocarcinoma, where lineage tracing indicates that Cytokeratin-Synaptophysin dual positive cells arise from the exocrine compartment. Mechanistically, MYC binding is enriched at neuroendocrine genes in mouse tumor cells and loss of MYC reduces ductal-neuroendocrine lineage heterogeneity, while deregulated MYC expression in KRAS mutant mice increases this phenotype. Neuroendocrine marker expression is associated with chemoresistance and reducing MYC levels decreases gemcitabine-induced neuroendocrine marker expression and increases chemosensitivity. Altogether, we demonstrate that MYC facilitates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma, contributing to poor survival and chemoresistance.

11 Article Epithelial-Myeloid cell crosstalk regulates acinar cell plasticity and pancreatic remodeling in mice. 2017

Zhang, Yaqing / Yan, Wei / Mathew, Esha / Kane, Kevin T / Brannon, Arthur / Adoumie, Maeva / Vinta, Alekya / Crawford, Howard C / Pasca di Magliano, Marina. ·Department of Surgery, University of Michigan, Ann Arbor, United States. · Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. · Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, United States. · Medical Scientist Training Program, University of Michigan, Ann Arbor, United States. · College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, United States. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States. · Department of Internal Medicine, University of Michigan, Ann Arbor, United States. · Comprehensive Cancer Center, University of Michigan, Ann Arbor, United States. · Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States. ·Elife · Pubmed #28980940.

ABSTRACT: Dedifferentiation of acini to duct-like cells occurs during the physiologic damage response in the pancreas, but this process can be co-opted by oncogenic Kras to drive carcinogenesis. Myeloid cells infiltrate the pancreas during the onset of pancreatic cancer, and promote carcinogenesis. Here, we show that the function of infiltrating myeloid cells is regulated by oncogenic Kras expressed in epithelial cells. In the presence of oncogenic Kras, myeloid cells promote acinar dedifferentiation and carcinogenesis. Upon inactivation of oncogenic Kras, myeloid cells promote re-differentiation of acinar cells, remodeling of the fibrotic stroma and tissue repair. Intriguingly, both aspects of myeloid cell activity depend, at least in part, on activation of EGFR/MAPK signaling, with different subsets of ligands and receptors in different target cells promoting carcinogenesis or repair, respectively. Thus, the cross-talk between epithelial cells and infiltrating myeloid cells determines the balance between tissue repair and carcinogenesis in the pancreas.

12 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.

13 Article NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. 2016

Chio, Iok In Christine / Jafarnejad, Seyed Mehdi / Ponz-Sarvise, Mariano / Park, Youngkyu / Rivera, Keith / Palm, Wilhelm / Wilson, John / Sangar, Vineet / Hao, Yuan / Öhlund, Daniel / Wright, Kevin / Filippini, Dea / Lee, Eun Jung / Da Silva, Brandon / Schoepfer, Christina / Wilkinson, John Erby / Buscaglia, Jonathan M / DeNicola, Gina M / Tiriac, Herve / Hammell, Molly / Crawford, Howard C / Schmidt, Edward E / Thompson, Craig B / Pappin, Darryl J / Sonenberg, Nahum / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA. · Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. · Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Institute of Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA. · Departments of Molecular & Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. · Division of Gastroenterology, Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA. · Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA. · Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59718, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: dtuveson@cshl.edu. ·Cell · Pubmed #27477511.

ABSTRACT: Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.

14 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.

15 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.

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

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

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

17 Article Loss of Activin Receptor Type 1B Accelerates Development of Intraductal Papillary Mucinous Neoplasms in Mice With Activated KRAS. 2016

Qiu, Wanglong / Tang, Sophia M / Lee, Sohyae / Turk, Andrew T / Sireci, Anthony N / Qiu, Anne / Rose, Christian / Xie, Chuangao / Kitajewski, Jan / Wen, Hui-Ju / Crawford, Howard C / Sims, Peter A / Hruban, Ralph H / Remotti, Helen E / Su, Gloria H. ·The Department of Pathology, Columbia University Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · The Department of Pathology, Columbia University Medical Center, New York, New York. · Plexus Medical Art, Denver, Colorado. · Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, New York. · Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, Florida. · Department of Systems Biology, Columbia University Medical Center, New York, New York. · The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland. · The Department of Pathology, Columbia University Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Department of Otolaryngology and Head and Neck Surgery, Columbia University Medical Center, New York, New York. Electronic address: gs2157@columbia.edu. ·Gastroenterology · Pubmed #26408346.

ABSTRACT: BACKGROUND & AIMS: Activin, a member of the transforming growth factor-β (TGFB) family, might be involved in pancreatic tumorigenesis, similar to other members of the TGFB family. Human pancreatic ductal adenocarcinomas contain somatic mutations in the activin A receptor type IB (ACVR1B) gene, indicating that ACVR1B could be a suppressor of pancreatic tumorigenesis. METHODS: We disrupted Acvr1b specifically in pancreata of mice (Acvr1b(flox/flox);Pdx1-Cre mice) and crossed them with LSL-KRAS(G12D) mice, which express an activated form of KRAS and develop spontaneous pancreatic tumors. The resulting Acvr1b(flox/flox);LSL-KRAS(G12D);Pdx1-Cre mice were monitored; pancreatic tissues were collected and analyzed by histology and immunohistochemical analyses. We also analyzed p16(flox/flox);LSL-Kras(G12D);Pdx1-Cre mice and Cre-negative littermates (controls). Genomic DNA, total RNA, and protein were isolated from mouse tissues and primary pancreatic tumor cell lines and analyzed by reverse-transcription polymerase chain reaction, sequencing, and immunoblot analyses. Human intraductal papillary mucinous neoplasm (IPMN) specimens were analyzed by immunohistochemistry. RESULTS: Loss of ACVR1B from pancreata of mice increased the proliferation of pancreatic epithelial cells, led to formation of acinar to ductal metaplasia, and induced focal inflammatory changes compared with control mice. Disruption of Acvr1b in LSL-KRAS(G12D);Pdx1-Cre mice accelerated the growth of pancreatic IPMNs compared with LSL-KRAS(G12D);Pdx1-Cre mice, but did not alter growth of pancreatic intraepithelial neoplasias. We associated perinuclear localization of the activated NOTCH4 intracellular domain to the apical cytoplasm of neoplastic cells with the expansion of IPMN lesions in Acvr1b(flox/flox);LSL-KRAS(G12D);Pdx1-Cre mice. Loss of the gene that encodes p16 (Cdkn2a) was required for progression of IPMNs to pancreatic ductal adenocarcinomas in Acvr1b(flox/flox);LSL-Kras(G12D);Pdx1-Cre mice. We also observed progressive loss of p16 in human IPMNs of increasing grades. CONCLUSIONS: Loss of ACVR1B accelerates growth of mutant KRAS-induced pancreatic IPMNs in mice; this process appears to involve NOTCH4 and loss of p16. ACVR1B suppresses early stages of pancreatic tumorigenesis; the activin signaling pathway therefore might be a therapeutic target for pancreatic cancer.

18 Article Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. 2015

Huang, Ling / Holtzinger, Audrey / Jagan, Ishaan / BeGora, Michael / Lohse, Ines / Ngai, Nicholas / Nostro, Cristina / Wang, Rennian / Muthuswamy, Lakshmi B / Crawford, Howard C / Arrowsmith, Cheryl / Kalloger, Steve E / Renouf, Daniel J / Connor, Ashton A / Cleary, Sean / Schaeffer, David F / Roehrl, Michael / Tsao, Ming-Sound / Gallinger, Steven / Keller, Gordon / Muthuswamy, Senthil K. ·Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada. · McEwen Center for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada. · Department of Physiology, Western University, London, Ontario, Canada. · Department of Pharmacology, Western University, London, Ontario, Canada. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. · Structural Genomics Consortium, Toronto, Ontario, Canada. · Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada. · Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada. · Pancreas Centre British Columbia, Vancouver, British Columbia, Canada. · Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Division of General Surgery, University of Toronto, Toronto, Ontario, Canada. · Department of Pathology, University Health Network, Toronto, Ontario, Canada. ·Nat Med · Pubmed #26501191.

ABSTRACT: There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

19 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.

20 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.

21 Article PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. 2014

Wu, Chia-Yen C / Carpenter, Eileen S / Takeuchi, Kenneth K / Halbrook, Christopher J / Peverley, Louise V / Bien, Harold / Hall, Jason C / DelGiorno, Kathleen E / Pal, Debjani / Song, Yan / Shi, Chanjuan / Lin, Richard Z / Crawford, Howard C. ·Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York. · Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida. · Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Department of Chemistry, Stony Brook University, Stony Brook, New York. · Division of Hematology/Oncology, Stony Brook University, Stony Brook, New York. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York; Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida. · Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Molecular Genetics and Microbiology Graduate Program, Stony Brook University, Stony Brook, New York. · Molecular and Cellular Biology Graduate Program, Stony Brook University, Stony Brook, New York. · Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York; Medical Service, Northport VA Medical Center, Northport, New York. Electronic address: richard.lin@stonybrook.edu. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York; Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida. Electronic address: crawford.howard@mayo.edu. ·Gastroenterology · Pubmed #25311989.

ABSTRACT: BACKGROUND & AIMS: New drug targets are urgently needed for the treatment of patients with pancreatic ductal adenocarcinoma (PDA). Nearly all PDAs contain oncogenic mutations in the KRAS gene. Pharmacological inhibition of KRAS has been unsuccessful, leading to a focus on downstream effectors that are more easily targeted with small molecule inhibitors. We investigated the contributions of phosphoinositide 3-kinase (PI3K) to KRAS-initiated tumorigenesis. METHODS: Tumorigenesis was measured in the Kras(G12D/+);Ptf1a(Cre/+) mouse model of PDA; these mice were crossed with mice with pancreas-specific disruption of genes encoding PI3K p110α (Pik3ca), p110β (Pik3cb), or RAC1 (Rac1). Pancreatitis was induced with 5 daily intraperitoneal injections of cerulein. Pancreata and primary acinar cells were isolated; acinar cells were incubated with an inhibitor of p110α (PIK75) followed by a broad-spectrum PI3K inhibitor (GDC0941). PDA cell lines (NB490 and MiaPaCa2) were incubated with PIK75 followed by GDC0941. Tissues and cells were analyzed by histology, immunohistochemistry, quantitative reverse-transcription polymerase chain reaction, and immunofluorescence analyses for factors involved in the PI3K signaling pathway. We also examined human pancreas tissue microarrays for levels of p110α and other PI3K pathway components. RESULTS: Pancreas-specific disruption of Pik3ca or Rac1, but not Pik3cb, prevented the development of pancreatic tumors in Kras(G12D/+);Ptf1a(Cre/+) mice. Loss of transformation was independent of AKT regulation. Preneoplastic ductal metaplasia developed in mice lacking pancreatic p110α but regressed. Levels of activated and total RAC1 were higher in pancreatic tissues from Kras(G12D/+);Ptf1a(Cre/+) mice compared with controls. Loss of p110α reduced RAC1 activity and expression in these tissues. p110α was required for the up-regulation and activity of RAC guanine exchange factors during tumorigenesis. Levels of p110α and RAC1 were increased in human pancreatic intraepithelial neoplasias and PDAs compared with healthy pancreata. CONCLUSIONS: KRAS signaling, via p110α to activate RAC1, is required for transformation in Kras(G12D/+);Ptf1a(Cre/+) mice.

22 Article Use of a preclinical model of pancreas cancer to identify potential candidates for rapalogue therapy. 2014

Takeuchi, Kenneth K / Crawford, Howard C. ·Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida, USA. ·Gut · Pubmed #24966285.

ABSTRACT: -- No abstract --

23 Article Tumor cell-derived MMP3 orchestrates Rac1b and tissue alterations that promote pancreatic adenocarcinoma. 2014

Mehner, Christine / Miller, Erin / Khauv, Davitte / Nassar, Aziza / Oberg, Ann L / Bamlet, William R / Zhang, Lizhi / Waldmann, Jens / Radisky, Evette S / Crawford, Howard C / Radisky, Derek C. ·Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224 U S A; · Department of Pathology, Mayo Clinic, Jacksonville, Florida; · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; · Department of Pathology, Mayo Clinic, Rochester, Minnesota; and. · Department of Visceral-, Thoracic- and Vascular Surgery, Unikliniken Marburg Und Giessen, Marburg, Germany. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224 U S A; radisky.derek@mayo.edu. ·Mol Cancer Res · Pubmed #24850902.

ABSTRACT: IMPLICATIONS: MMP3 acts as a coconspirator of oncogenic KRAS in pancreatic cancer tumorigenesis and progression, both through Rac1b-mediated phenotypic control of pancreatic cancer cells themselves, and by giving rise to the tumorigenic microenvironment; these findings also point to inhibition of this pathway as a potential therapeutic strategy for pancreatic cancer.

24 Article Identification and manipulation of biliary metaplasia in pancreatic tumors. 2014

Delgiorno, Kathleen E / Hall, Jason C / Takeuchi, Kenneth K / Pan, Fong Cheng / Halbrook, Christopher J / Washington, M Kay / Olive, Kenneth P / Spence, Jason R / Sipos, Bence / Wright, Christopher V E / Wells, James M / Crawford, Howard C. ·Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York; Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. · Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York. · Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. · Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee. · Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. · Department of Pathology, University Hospital Tubingen, Tubingen, Germany. · Department of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. · Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York; Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. Electronic address: crawford.howard@mayo.edu. ·Gastroenterology · Pubmed #23999170.

ABSTRACT: BACKGROUND & AIMS: Metaplasias often have characteristics of developmentally related tissues. Pancreatic metaplastic ducts are usually associated with pancreatitis and pancreatic ductal adenocarcinoma. The tuft cell is a chemosensory cell that responds to signals in the extracellular environment via effector molecules. Commonly found in the biliary tract, tuft cells are absent from normal murine pancreas. Using the aberrant appearance of tuft cells as an indicator, we tested if pancreatic metaplasia represents transdifferentiation to a biliary phenotype and what effect this has on pancreatic tumorigenesis. METHODS: We analyzed pancreatic tissue and tumors that developed in mice that express an activated form of Kras (Kras(LSL-G12D/+);Ptf1a(Cre/+) mice). Normal bile duct, pancreatic duct, and tumor-associated metaplasias from the mice were analyzed for tuft cell and biliary progenitor markers, including SOX17, a transcription factor that regulates biliary development. We also analyzed pancreatic tissues from mice expressing transgenic SOX17 alone (ROSA(tTa/+);Ptf1(CreERTM/+);tetO-SOX17) or along with activated Kras (ROSAtT(a/+);Ptf1a(CreERTM/+);tetO-SOX17;Kras(LSL-G12D;+)). RESULTS: Tuft cells were frequently found in areas of pancreatic metaplasia, decreased throughout tumor progression, and absent from invasive tumors. Analysis of the pancreatobiliary ductal systems of mice revealed tuft cells in the biliary tract but not the normal pancreatic duct. Analysis for biliary markers revealed expression of SOX17 in pancreatic metaplasia and tumors. Pancreas-specific overexpression of SOX17 led to ductal metaplasia along with inflammation and collagen deposition. Mice that overexpressed SOX17 along with Kras(G12D) had a greater degree of transformed tissue compared with mice expressing only Kras(G12D). Immunofluorescence analysis of human pancreatic tissue arrays revealed the presence of tuft cells in metaplasia and early-stage tumors, along with SOX17 expression, consistent with a biliary phenotype. CONCLUSIONS: Expression of Kras(G12D) and SOX17 in mice induces development of metaplasias with a biliary phenotype containing tuft cells. Tuft cells express a number of tumorigenic factors that can alter the microenvironment. Expression of SOX17 induces pancreatitis and promotes Kras(G12D)-induced tumorigenesis in mice.

25 Article Heparin-binding epidermal growth factor-like growth factor eliminates constraints on activated Kras to promote rapid onset of pancreatic neoplasia. 2014

Ray, K C / Moss, M E / Franklin, J L / Weaver, C J / Higginbotham, J / Song, Y / Revetta, F L / Blaine, S A / Bridges, L R / Guess, K E / Coffey, R J / Crawford, H C / Washington, M K / Means, A L. ·Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. · 1] Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA. · Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA. · 1] Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA [2] Department of Research, Veterans Affairs Medical Center, Northport, NY, USA. · 1] Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA. ·Oncogene · Pubmed #23376846.

ABSTRACT: Pancreatic cancer remains as one of the most deadly cancers with few treatment options at late stages and little information about how it develops through earlier stages. Activating mutation of the Kras gene has been implicated in, but is not sufficient for, tumorigenesis. In mouse models of pancreatic cancer, loss of tumor suppressor genes in conjunction with Kras mutation leads to gradual stochastic acquisition of neoplastic precursors and carcinomas, whereas many cells remain phenotypically unaltered in younger mice. Here, we demonstrate that two oncogenic events, mutation of Kras and production of the growth factor heparin-binding epidermal growth factor-like growth factor (HB-EGF), are sufficient for rapid and complete neoplastic transformation of the exocrine pancreas. We found that macrophages are the major source of HB-EGF production in pancreatic cancer tissue samples, and that macrophages are present in high density and in close association with human pancreatic cancer lesions. In a mouse model, high macrophage density was observed at the earliest stages of neoplastic transformation. The consequence of elevated HB-EGF signaling was investigated without the confounding effects of other macrophage-produced factors via transgenic overexpression of the active form of HB-EGF. In this model, HB-EGF was sufficient to promote Kras-initiated tumorigenesis, inducing rapid and complete neoplastic transformation of the entire exocrine pancreas shortly after birth. HB-EGF overexpression and Kras(G12D) together, but neither alone, increased proliferation with increased cyclinD1 and decreased Cdkn2a/2d (p16/p19(Ink4A/Arf)). These findings establish the importance of oncogenic synergy in cancer initiation and promotion, and establish a molecular link between inflammation and the earliest stages of tumor induction.

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