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Pancreatic Neoplasms: HELP
Articles by Jennifer M. Bailey
Based on 17 articles published since 2010
(Why 17 articles?)
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Between 2010 and 2020, J. M. Bailey wrote the following 17 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Editorial New insights into plasticity of pancreatic cancer: cancer to acinar cell reprogramming by the basic helix-loop-helix transcription factor E47. 2015

Bailey, Jennifer M / Hendley, Audrey M / Maitra, Anirban. ·From the *Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston; and †Departments of Pathology and Molecular Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. ·Pancreas · Pubmed #26061556.

ABSTRACT: -- No abstract --

2 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.

3 Review Molecular pathology of early pancreatic cancer. 2010

Remmers, Neeley / Bailey, Jennifer M / Mohr, Ashley M / Hollingsworth, Michael A. ·Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. ·Cancer Biomark · Pubmed #22112488.

ABSTRACT: We describe the pathology of early pancreatic cancer and present an overview of known molecular alterations that occur in these lesions. There are three defined precursor lesions in current models of pancreatic cancer: pancreatic intraepithelial neoplasia (PanIN), mucinous cystic neoplasms (MCN), and intraductal papillary mucinous neoplasms (IPMN). Molecular alterations detected in these lesions include: telomeres, K-ras and downstream targets, p16/CDKN2A, p53, SMAD4/DPC4, microRNAs, mucins and their post-translational processing, inflammatory cytokines, CEACAM, and epigenetic alterations. We summarize previous analyses of these markers as diagnostic markers of disease, and suggest areas of future study.

4 Article Mutant p53 2019

Polireddy, Kishore / Singh, Kanchan / Pruski, Melissa / Jones, Neal C / Manisundaram, Naveen V / Ponnela, Pavani / Ouellette, Michel / Van Buren, George / Younes, Mamoun / Bynon, John S / Dar, Wasim A / Bailey, Jennifer M. ·Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Texas McGovern Medical School, Houston, TX, 77030, USA. · Division of Immunology and Organ Transplantation, Department of Surgery, The University of Texas McGovern Medical School, Houston, TX, 77030, USA. · Division of Gastroenterology, Department of Internal Medicine, The University of Nebraska Medical Center, Omaha, NE, 68198, USA. · Division of Surgical Oncology, Department of Surgery, Baylor College of Medicine, Houston, TX, 77030, USA. · Division of Pathology and Laboratory Medicine, The University of Texas McGovern Medical School, Houston, TX, 77030, USA. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Texas McGovern Medical School, Houston, TX, 77030, USA. Electronic address: Jennifer.M.Bailey@uth.tmc.edu. ·Cancer Lett · Pubmed #30946870.

ABSTRACT: Pancreatic cancer remains a highly lethal malignancy. We have recently shown that simultaneous expression of Kras and mutant Tp53

5 Article Immune Cell Production of Interleukin 17 Induces Stem Cell Features of Pancreatic Intraepithelial Neoplasia Cells. 2018

Zhang, Yu / Zoltan, Michelle / Riquelme, Erick / Xu, Hanwen / Sahin, Ismet / Castro-Pando, Susana / Montiel, Maria Fernanda / Chang, Kyle / Jiang, Zhengyu / Ling, Jianhua / Gupta, Sonal / Horne, William / Pruski, Melissa / Wang, Huamin / Sun, Shao-Cong / Lozano, Guillermina / Chiao, Paul / Maitra, Anirban / Leach, Steven D / Kolls, Jay K / Vilar, Eduardo / Wang, Timothy C / Bailey, Jennifer M / McAllister, Florencia. ·Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Engineering, Texas Southern University, Houston, Texas. · Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas. · Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. · Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Texas Health Science Center, Houston, Texas. · Department of Immunology, University of Texas Health Sciences Center, Houston, Texas. · Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: fmcallister@mdanderson.org. ·Gastroenterology · Pubmed #29604293.

ABSTRACT: BACKGROUND & AIMS: Little is known about how the immune system affects stem cell features of pancreatic cancer cells. Immune cells that produce interleukin 17A (IL17A) in the chronically inflamed pancreas (chronic pancreatitis) contribute to pancreatic interepithelial neoplasia (PanIN) initiation and progression. We investigated the effects that IL17A signaling exerts on pancreatic cancer progenitor cells and the clinical relevance of this phenomena. METHODS: We performed studies with Mist1Cre;LSLKras;Rosa26mTmG (KC RESULTS: PanIN cells from KC CONCLUSIONS: In studies of mouse and human pancreatic tumors and precursors, we found that immune cell-derived IL17 regulated development of tuft cells and stem cell features of pancreatic cancer cells via increased expression of DCLK1, POU2F3, ALDH1A1, and IL17RC. Strategies to disrupt this pathway might be developed to prevent pancreatic tumor growth and progression.

6 Article PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk. 2017

Sinha, Smrita / Fu, Ya-Yuan / Grimont, Adrien / Ketcham, Maren / Lafaro, Kelly / Saglimbeni, Joseph A / Askan, Gokce / Bailey, Jennifer M / Melchor, Jerry P / Zhong, Yi / Joo, Min Geol / Grbovic-Huezo, Olivera / Yang, In-Hong / Basturk, Olca / Baker, Lindsey / Park, Young / Kurtz, Robert C / Tuveson, David / Leach, Steven D / Pasricha, Pankaj J. ·David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. · Gastroenterology and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Gastroenterology and Hepatology, Johns Hopkins Hospital, Baltimore, Maryland. · Weill Cornell Medical College, New York, New York. · Gastrointestinal Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Surgical Oncology, Johns Hopkins Hospital, Baltimore, Maryland. · Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. leachs@mskcc.org ppasric1@jhmi.edu. · Division of Gastroenterology and Hepatology, Johns Hopkins Hospital, Baltimore, Maryland. leachs@mskcc.org ppasric1@jhmi.edu. ·Cancer Res · Pubmed #28386018.

ABSTRACT: Nerves are a notable feature of the tumor microenvironment in some epithelial tumors, but their role in the malignant progression of pancreatic ductal adenocarcinoma (PDAC) is uncertain. Here, we identify dense innervation in the microenvironment of precancerous pancreatic lesions, known as pancreatic intraepithelial neoplasms (PanIN), and describe a unique subpopulation of neuroendocrine PanIN cells that express the neuropeptide substance P (SP) receptor neurokinin 1-R (NK1-R). Using organoid culture, we demonstrated that sensory neurons promoted the proliferation of PanIN organoids via SP-NK1-R signaling and STAT3 activation. Nerve-responsive neuroendocrine cells exerted trophic influences and potentiated global PanIN organoid growth. Sensory denervation of a genetically engineered mouse model of PDAC led to loss of STAT3 activation, a decrease in the neoplastic neuroendocrine cell population, and impaired PanIN progression to tumor. Overall, our data provide evidence that nerves of the PanIN microenvironment promote oncogenesis, likely via direct signaling to neoplastic neuroendocrine cells capable of trophic influences. These findings identify neuroepithelial cross-talk as a potential novel target in PDAC treatment.

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

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

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

8 Article p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells. 2016

Bailey, J M / Hendley, A M / Lafaro, K J / Pruski, M A / Jones, N C / Alsina, J / Younes, M / Maitra, A / McAllister, F / Iacobuzio-Donahue, C A / Leach, S D. ·Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, Houston, TX, USA. · The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA. · Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Departments of Clinical Cancer Prevention and GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ·Oncogene · Pubmed #26592447.

ABSTRACT: Pancreatic cancer is one of the most lethal malignancies, with virtually all patients eventually succumbing to their disease. Mutations in p53 have been documented in >50% of pancreatic cancers. Owing to the high incidence of p53 mutations in PanIN 3 lesions and pancreatic tumors, we interrogated the comparative ability of adult pancreatic acinar and ductal cells to respond to oncogenic Kras and mutant Tp53(R172H) using Hnf1b:CreER(T2) and Mist1:CreER(T2) mice. These studies involved co-activation of a membrane-tethered GFP lineage label, allowing for direct visualization and isolation of cells undergoing Kras and mutant p53 activation. Kras activation in Mist1(+) adult acinar cells resulted in brisk PanIN formation, whereas no evidence of pancreatic neoplasia was observed for up to 6 months following Kras activation in Hnf1beta(+) adult ductal cells. In contrast to the lack of response to oncogenic Kras alone, simultaneous activation of Kras and mutant p53 in adult ductal epithelium generated invasive PDAC in 75% of mice as early as 2.5 months after tamoxifen administration. These data demonstrate that pancreatic ductal cells, whereas exhibiting relative resistance to oncogenic Kras alone, can serve as an effective cell of origin for pancreatic ductal adenocarcinoma in the setting of gain-of-function mutations in p53.

9 Article Dicer is required for maintenance of adult pancreatic acinar cell identity and plays a role in Kras-driven pancreatic neoplasia. 2014

Wang, Yue J / McAllister, Florencia / Bailey, Jennifer M / Scott, Sherri-Gae / Hendley, Audrey M / Leach, Steven D / Ghosh, Bidyut. ·The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. · The Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. · The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; The Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. · The Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. · The Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. ·PLoS One · Pubmed #25405615.

ABSTRACT: The role of miRNA processing in the maintenance of adult pancreatic acinar cell identity and during the initiation and progression of pancreatic neoplasia has not been studied in detail. In this work, we deleted Dicer specifically in adult pancreatic acinar cells, with or without simultaneous activation of oncogenic Kras. We found that Dicer is essential for the maintenance of acinar cell identity. Acinar cells lacking Dicer showed increased plasticity, as evidenced by loss of polarity, initiation of epithelial-to-mesenchymal transition (EMT) and acinar-to-ductal metaplasia (ADM). In the context of oncogenic Kras activation, the initiation of ADM and pancreatic intraepithelial neoplasia (PanIN) were both highly sensitive to Dicer gene dosage. Homozygous Dicer deletion accelerated the formation of ADM but not PanIN. In contrast, heterozygous Dicer deletion accelerated PanIN initiation, revealing complex roles for Dicer in the regulation of both normal and neoplastic pancreatic epithelial identity.

10 Article The tumor suppressor rpl36 restrains KRAS(G12V)-induced pancreatic cancer. 2014

Provost, Elayne / Bailey, Jennifer M / Aldrugh, Sumar / Liu, Shu / Iacobuzio-Donahue, Christine / Leach, Steven D. ·1 Department of Surgery, Johns Hopkins University , Baltimore, Maryland. ·Zebrafish · Pubmed #25380065.

ABSTRACT: Ribosomal proteins are known to be required for proper assembly of mature ribosomes. Recent studies indicate an additional role for ribosomal proteins as candidate tumor suppressor genes. Pancreatic acinar cells, recently identified as effective cells of origin for pancreatic adenocarcinoma, display especially high-level expression of multiple ribosomal proteins. We, therefore, functionally interrogated the ability of two ribosomal proteins, rpl36 and rpl23a, to alter the response to oncogenic Kras in pancreatic acinar cells using a newly established model of zebrafish pancreatic cancer. These studies reveal that rpl36, but not rpl23a, acts as a haploinsufficient tumor suppressor, as manifested by more rapid tumor progression and decreased survival in rpl36(hi1807/+);ptf1a:gal4VP16(Tg);UAS:GFP-KRAS(G12V) fish compared with their rpl36(+/+);ptf1a:gal4VP16;UAS:GFP-KRAS(G12V) siblings. These results suggest that rpl36 may function as an effective tumor suppressor during pancreatic tumorigenesis.

11 Article Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. 2014

McAllister, Florencia / Bailey, Jennifer M / Alsina, Janivette / Nirschl, Christopher J / Sharma, Rajni / Fan, Hongni / Rattigan, Yanique / Roeser, Jeffrey C / Lankapalli, Rachana H / Zhang, Hao / Jaffee, Elizabeth M / Drake, Charles G / Housseau, Franck / Maitra, Anirban / Kolls, Jay K / Sears, Cynthia L / Pardoll, Drew M / Leach, Steven D. ·Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA; Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. · Department of Surgery and McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. · Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21205, USA. · Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. · Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21205, USA. · Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA. · Department of Surgery and McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: leachs@mskcc.org. ·Cancer Cell · Pubmed #24823639.

ABSTRACT: Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of pancreatic intraepithelial neoplasia (PanIN), we found that Kras(G12D) induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional in vivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.

12 Article DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. 2014

Bailey, Jennifer M / Alsina, Janivette / Rasheed, Zeshaan A / McAllister, Florencia M / Fu, Ya-Yuan / Plentz, Ruben / Zhang, Hao / Pasricha, Pankaj J / Bardeesy, Nabeel / Matsui, William / Maitra, Anirban / Leach, Steven D. ·Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Department of Internal Medicine, Medical University Hospital, Tuebingen, Germany. · Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. · Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: stleach@jhmi.edu. ·Gastroenterology · Pubmed #24096005.

ABSTRACT: BACKGROUND & AIMS: As in other tumor types, progression of pancreatic cancer may require a functionally unique population of cancer stem cells. Although such cells have been identified in many invasive cancers, it is not clear whether they emerge during early or late stages of tumorigenesis. Using mouse models and human pancreatic cancer cell lines, we investigated whether preinvasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell-like properties. METHODS: Pancreatic tissue samples were collected from the KC(Pdx1), KPC(Pdx1), and KC(iMist1) mouse models of pancreatic intraepithelial neoplasia (PanIN) and analyzed by confocal and electron microscopy, lineage tracing, and fluorescence-activated cell sorting. Subpopulations of human pancreatic ductal adenocarcinoma (PDAC) cells were similarly analyzed and also used in complementary DNA microarray analyses. RESULTS: The microtubule regulator DCLK1 marked a morphologically distinct and functionally unique population of pancreatic cancer-initiating cells. These cells displayed morphological and molecular features of gastrointestinal tuft cells. Cells that expressed DCLK1 also expressed high levels of ATAT1, HES1, HEY1, IGF1R, and ABL1, and manipulation of these pathways in PDAC cell lines inhibited their clonogenic potential. Pharmacological inhibition of γ-secretase activity reduced the abundance of these cells in murine PanIN in a manner that correlated with inhibition of PanIN progression. CONCLUSIONS: Human PDAC cells and pancreatic neoplasms in mice contain morphologically and functionally distinct subpopulations that have cancer stem cell-like properties. These populations can be identified at the earliest stages of pancreatic tumorigenesis and provide new cellular and molecular targets for pancreatic cancer treatment and/or chemoprevention.

13 Article MUC1 regulates expression of multiple microRNAs involved in pancreatic tumor progression, including the miR-200c/141 cluster. 2013

Mohr, Ashley M / Bailey, Jennifer M / Lewallen, Michelle E / Liu, Xiang / Radhakrishnan, Prakash / Yu, Fang / Tapprich, William / Hollingsworth, Michael A. ·Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America. ·PLoS One · Pubmed #24143167.

ABSTRACT: MUC1 is a transmembrane glycoprotein that modulates transcription via its cytoplasmic domain. We evaluated the capacity of MUC1 to regulate the global transcription of microRNAs in pancreatic cancer cells expressing MUC1. Results indicated that MUC1 regulated expression of at least 103 microRNAs. We evaluated further regulation of the microRNA transcript cluster miR-200c/141, which was among the most highly regulated microRNAs. We found that MUC1 directly interacted with ZEB1, a known transcriptional repressor of the miR-200c/141 cluster, at the promoter of miR-200c/141, and further reduced transcript production. These data indicate that signaling through MUC1 influences cancer progression by regulating transcription of microRNAs that are associated with the process of metastasis.

14 Article Sphere-forming assays for assessment of benign and malignant pancreatic stem cells. 2013

Wang, Yue J / Bailey, Jennifer M / Rovira, Meritxell / Leach, Steven D. ·McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA. ·Methods Mol Biol · Pubmed #23359160.

ABSTRACT: Sphere-forming assays are an in vitro technique to assay both normal and neoplastic cells for clonogenic growth potential. Currently, the identification of adult progenitors in the pancreas remains an area of intense investigation. The use of sphere-forming assays provides a critical step to identify new cell types in the pancreas that are capable of clonogenic growth and differentiation. In the field of cancer biology, cancer stem cells have been defined functionally by two major criteria: their ability to undergo self-renewal and their ability to produce differentiated progeny, two conditions which satisfy the criteria of stem cells. Here we briefly review both the capabilities of pancreatosphere and pancreatic tumorsphere assays, discuss important caveats regarding their use, and provide detailed protocols for the assay of both normal and neoplastic cells.

15 Article Rosiglitazone and Gemcitabine in combination reduces immune suppression and modulates T cell populations in pancreatic cancer. 2013

Bunt, Stephanie K / Mohr, Ashley M / Bailey, Jennifer M / Grandgenett, Paul M / Hollingsworth, Michael A. ·Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA. ·Cancer Immunol Immunother · Pubmed #22864396.

ABSTRACT: Pancreatic ductal adenocarcinoma is a leading cause of cancer mortality with a dismal 2-5 % 5-year survival rate. Monotherapy with Gemcitabine has limited success, highlighting the need for additional therapies that enhance the efficacy of current treatments. We evaluated the combination of Gemcitabine and Rosiglitazone, an FDA-approved drug for the treatment of type II diabetes, in an immunocompetent transplantable mouse model of pancreatic cancer. Tumor progression, survival, and metastases were evaluated in immunocompetent mice with subcutaneous or orthotopic pancreatic tumors treated with Pioglitazone, Rosiglitazone, Gemcitabine, or combinations of these. We characterized the impact of high-dose Rosiglitazone and Gemcitabine therapy on immune suppressive mediators, including MDSC and T regulatory cells, and on modulation of peripheral and intra-tumoral T cell populations. Combinations of Rosiglitazone and Gemcitabine significantly reduced tumor progression and metastases, enhanced apoptosis, and significantly extended overall survival compared to Gemcitabine alone. Rosiglitazone altered tumor-associated immune suppressive mediators by limiting early MDSC accumulation and intra-tumoral T regulatory cells. Combination therapy with Rosiglitazone and Gemcitabine modulated T cell populations by enhancing circulating CD8(+) T cells and intra-tumoral CD4(+) and CD8(+) T cells while limiting T regulatory cells. The results suggest that Rosiglitazone, in combination with Gemcitabine, decreases immune suppressive mechanisms in immunocompetent animals and provides pre-clinical data in support of combining Rosiglitazone and Gemcitabine as a clinical therapy for pancreatic cancer.

16 Article EMT and dissemination precede pancreatic tumor formation. 2012

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

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

17 Article The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. 2010

Behrens, M E / Grandgenett, P M / Bailey, J M / Singh, P K / Yi, C-H / Yu, F / Hollingsworth, M A. ·Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA. ·Oncogene · Pubmed #20697347.

ABSTRACT: The MUC1 cytoplasmic tail (MUC1.CT) conducts signals from spatial and extracellular cues (growth factor and cytokine stimulation) to evoke a reprogramming of the cellular transcriptional profile. Specific phosphorylated forms of the MUC1.CT achieve this function by differentially associating with transcription factors and redirecting their transcriptional regulatory capabilities at specific gene regulatory elements. The specificity of interaction between MUC1.CT and several transcription factors is dictated by the phosphorylation pattern of the 18 potential phosphorylation motifs within the MUC1.CT. To better appreciate the scope of differential gene expression triggered by MUC1.CT activation, we performed microarray gene expression analysis and chromatin immunoprecipitation (ChIP)-chip promoter analysis and identified the genome-wide transcriptional targets of MUC1.CT signaling in pancreatic cancer. On a global scale, MUC1.CT preferentially targets genes related to invasion, angiogenesis and metastasis, suggesting that MUC1.CT signaling contributes to establishing a reactive tumor microenvironment during tumor progression to metastatic disease. We examined in detail the molecular mechanisms of MUC1.CT signaling that induces the expression of connective tissue growth factor (CTGF/CCN2), a potent mediator of ECM remodeling and angiogenesis. We demonstrate a robust induction of CTGF synthesis and secretion in response to serum factors that is enabled only when MUC1 is highly expressed. We demonstrate the requirement of phosphorylation at distinct tyrosine motifs within the MUC1.CT for MUC1-induced CTGF expression and demonstrate a phosphorylation-specific localization of MUC1.CT to the CTGF promoter. We found that MUC1 reorganizes transcription factor occupancy of genomic regions upstream of the CTGF gene, directing β-catenin and mutant p53 to CTGF gene regulatory elements to promote CTGF expression and destabilizing the interaction at these regions of the transcriptional repressor, c-Jun. With this example we illustrate the capacity of MUC1.CT to mediate transcription factor activity in a context-dependent manner to achieve wide spread and robust changes in gene expression and facilitate creation of the reactive tumor microenvironment.