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Acinar ductal metaplasia

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https://www.readbyqxmd.com/read/28270694/acinar-cell-plasticity-and-development-of-pancreatic-ductal-adenocarcinoma
#1
REVIEW
Peter Storz
Acinar cells in the adult pancreas show high plasticity and can undergo transdifferentiation to a progenitor-like cell type with ductal characteristics. This process, termed acinar-to-ductal metaplasia (ADM), is an important feature facilitating pancreas regeneration after injury. Data from animal models show that cells that undergo ADM in response to oncogenic signalling are precursors for pancreatic intraepithelial neoplasia lesions, which can further progress to pancreatic ductal adenocarcinoma (PDAC). As human pancreatic adenocarcinoma is often diagnosed at a stage of metastatic disease, understanding the processes that lead to its initiation is important for the discovery of markers for early detection, as well as options that enable an early intervention...
March 8, 2017: Nature Reviews. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28162998/common-telomere-changes-during-in%C3%A2-vivo-reprogramming-and-early-stages-of-tumorigenesis
#2
Rosa M Marión, Isabel López de Silanes, Lluc Mosteiro, Benjamin Gamache, María Abad, Carmen Guerra, Diego Megías, Manuel Serrano, Maria A Blasco
Reprogramming of differentiated cells into induced pluripotent stem cells has been recently achieved in vivo in mice. Telomeres are essential for chromosomal stability and determine organismal life span as well as cancer growth. Here, we study whether tissue dedifferentiation induced by in vivo reprogramming involves changes at telomeres. We find telomerase-dependent telomere elongation in the reprogrammed areas. Notably, we found highly upregulated expression of the TRF1 telomere protein in the reprogrammed areas, which was independent of telomere length...
February 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28099259/smad2-3-linker-phosphorylation-is-a-possible-marker-of-pancreatic-stem-progenitor-cells-in-the-regenerative-phase-of-acute-pancreatitis
#3
Masayuki Sakao, Yutaku Sakaguchi, Ryo Suzuki, Yu Takahashi, Masanobu Kishimoto, Toshiro Fukui, Kazushige Uchida, Akiyoshi Nishio, Koichi Matsuzaki, Kazuichi Okazaki
OBJECTIVES: The aims of this study are to characterize cell proliferation and differentiation during regeneration after pancreatitis and pancreatic buds during development to evaluate the role of Smad2/3, phosphorylated at the specific linker threonine residues (pSmad2/3L-Thr) in positive cells. METHODS: Male C57BL/6 mice received hourly intraperitoneal injections of cerulein and were analyzed after induced pancreatitis. Pancreatitis-affected tissue sections and pancreatic buds were immunostained for pSmad2/3L-Thr, with other markers thought to be stem/progenitor markers of the pancreas...
January 18, 2017: Pancreas
https://www.readbyqxmd.com/read/28090569/mitogen-activated-protein-kinase-kinase-activity-maintains-acinar-to-ductal-metaplasia-and-is-required-for-organ-regeneration-in-pancreatitis
#4
Christopher J Halbrook, Hui-Ju Wen, Jeanine M Ruggeri, Kenneth K Takeuchi, Yaqing Zhang, Marina Pasca di Magliano, Howard C Crawford
BACKGROUND & AIMS: Mitogen-activated protein kinase (MAPK) signaling in the exocrine pancreas has been extensively studied in the context of pancreatic cancer, where its potential as a therapeutic target is limited by acquired drug resistance. However, its role in pancreatitis is less understood. We investigated the role of mitogen-activated protein kinase kinase (MEK)-initiated MAPK signaling in pancreatitis to determine the potential for MEK inhibition in treating pancreatitis patients...
January 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28089234/oncogenic-kras-induced-increase-in-fluid-phase-endocytosis-is-dependent-on-n-wasp-and-is-required-for-the-formation-of-pancreatic-preneoplastic-lesions
#5
Clara Lubeseder-Martellato, Katharina Alexandrow, Ana Hidalgo-Sastre, Irina Heid, Sophie Luise Boos, Thomas Briel, Roland M Schmid, Jens T Siveke
Fluid-phase endocytosis is a homeostatic process with an unknown role in tumor initiation. The driver mutation in pancreatic ductal adenocarcinoma (PDAC) is constitutively active KRas(G12D), which induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). We have previously shown that KRas(G12D)-induced ADM is dependent on RAC1 and EGF receptor (EGFR) by a not fully clarified mechanism. Using three-dimensional mouse and human acinar tissue cultures and genetically engineered mouse models, we provide evidence that (i) KRas(G12D) leads to EGFR-dependent sustained fluid-phase endocytosis (FPE) during acinar metaplasia; (ii) variations in plasma membrane tension increase FPE and lead to ADM in vitro independently of EGFR; and (iii) that RAC1 regulates ADM formation partially through actin-dependent regulation of FPE...
December 24, 2016: EBioMedicine
https://www.readbyqxmd.com/read/28057438/oncogenic-kras-induced-increase-in-fluid-phase-endocytosis-is-dependent-on-n-wasp-and-is-required-for-the-formation-of-pancreatic-preneoplastic-lesions
#6
Clara Lubeseder-Martellato, Katharina Alexandrow, Ana Hidalgo-Sastre, Irina Heid, Sophie Luise Boos, Thomas Briel, Roland M Schmid, Jens T Siveke
Fluid-phase endocytosis is a homeostatic process with an unknown role in tumor initiation. The driver mutation in pancreatic ductal adenocarcinoma (PDAC) is constitutively active KRas(G12D), which induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). We have previously shown that KRas(G12D)-induced ADM is dependent on RAC1 and EGF receptor (EGFR) by a not fully clarified mechanism. Using three-dimensional mouse and human acinar tissue cultures and genetically engineered mouse models, we provide evidence that (i) KRas(G12D) leads to EGFR-dependent sustained fluid-phase endocytosis (FPE) during acinar metaplasia; (ii) variations in plasma membrane tension increase FPE and lead to ADM in vitro independently of EGFR; and (iii) that RAC1 regulates ADM formation partially through actin-dependent regulation of FPE...
February 2017: EBioMedicine
https://www.readbyqxmd.com/read/27851966/pancreatic-inflammation-redirects-acinar-to-%C3%AE-cell-reprogramming
#7
Hannah W Clayton, Anna B Osipovich, Jennifer S Stancill, Judsen D Schneider, Pedro G Vianna, Carolyn M Shanks, Weiping Yuan, Guoqiang Gu, Elisabetta Manduchi, Christian J Stoeckert, Mark A Magnuson
Using a transgenic mouse model to express MafA, Pdx1, and Neurog3 (3TF) in a pancreatic acinar cell- and doxycycline-dependent manner, we discovered that the outcome of transcription factor-mediated acinar to β-like cellular reprogramming is dependent on both the magnitude of 3TF expression and on reprogramming-induced inflammation. Overly robust 3TF expression causes acinar cell necrosis, resulting in marked inflammation and acinar-to-ductal metaplasia. Generation of new β-like cells requires limiting reprogramming-induced inflammation, either by reducing 3TF expression or by eliminating macrophages...
November 15, 2016: Cell Reports
https://www.readbyqxmd.com/read/27798096/chronic-pancreatitis-and-lipomatosis-are-associated-with-defective-function-of-ciliary-genes-in-pancreatic-ductal-cells
#8
Cécile Augereau, Louis Collet, Pierfrancesco Vargiu, Carmen Guerra, Sagrario Ortega, Frédéric P Lemaigre, Patrick Jacquemin
Genetic diseases associated with defects in primary cilia are classified as ciliopathies. Pancreatic lesions and ductal cysts are found in patients with ciliopathic polycystic kidney diseases suggesting a close connection between pancreatic defects and primary cilia. Here we investigate the role of two genes whose deletion is known to cause primary cilium defects, namely Hnf6 and Lkb1, in pancreatic ductal homeostasis. We find that mice with postnatal duct-specific deletion of Hnf6 or Lkb1 show duct dilations...
October 7, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27788482/reg-proteins-promote-acinar-to-ductal-metaplasia-and-act-as-novel-diagnostic-and-prognostic-markers-in-pancreatic-ductal-adenocarcinoma
#9
Qing Li, Hao Wang, George Zogopoulos, Qin Shao, Kun Dong, Fudong Lv, Karam Nwilati, Xian-Yong Gui, Adeline Cuggia, Jun-Li Liu, Zu-Hua Gao
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor. Acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) are both precursor lesions that lead to the development of PDAC. Reg family proteins (Reg1A, 1B, 3A/G, 4) are a group of calcium-dependent lectins that promote islet growth in response to inflammation and/or injuries. The aim of this study was to establish a role for Reg proteins in the development of PDAC and their clinical value as biomarkers. We found that Reg1A and Reg3A/G were highly expressed in the ADM tissues by immunohistochemistry...
October 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27764699/fbxw7-deletion-accelerates-kras-g12d-driven-pancreatic-tumorigenesis-via-yap-accumulation
#10
Qiang Zhang, Yaqing Zhang, Joshua D Parsels, Ines Lohse, Theodore S Lawrence, Marina Pasca di Magliano, Yi Sun, Meredith A Morgan
Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-Kras(G12D);Fbxw7(fl/fl) (KFC(fl/fl)) compound mice. We found that KFC(fl/fl) mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age...
November 2016: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/27697859/transcriptional-maintenance-of-pancreatic-acinar-identity-differentiation-and-homeostasis-by-ptf1a
#11
Chinh Q Hoang, Michael A Hale, Ana C Azevedo-Pouly, Hans P Elsässer, Tye G Deering, Spencer G Willet, Fong C Pan, Mark A Magnuson, Christopher V E Wright, Galvin H Swift, Raymond J MacDonald
Maintenance of cell type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo Transcriptome sequencing and chromatin immunoprecipitation sequencing results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR)...
December 15, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27664234/pancreatic-fibroblasts-smoothen-their-activities-via-akt-gli2-tgf%C3%AE
#12
Anil K Rustgi
Pancreatic stromal fibroblasts provide structural support. Activated fibroblasts are critical in the tumor microenvironment. In this issue of Genes & Development, Liu and colleagues (pp. 1943-1955) unravel the finding that depletion of Smoothened (Smo) in pancreatic stromal fibroblasts results in AKT activation and noncanonical GLI2 activation with subsequent TGFα secretion, activation of EGFR in pancreatic epithelial cells, and augmentation of acinar-ductal metaplasia. Additionally, Smo-mediated signaling has proproliferative effects on pancreatic tumor cells...
September 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27659014/stromal-ets2-regulates-chemokine-production-and-immune-cell-recruitment-during-acinar-to-ductal-metaplasia
#13
Jason R Pitarresi, Xin Liu, Sudarshana M Sharma, Maria C Cuitiño, Raleigh D Kladney, Thomas A Mace, Sydney Donohue, Sunayana G Nayak, Chunjing Qu, James Lee, Sarah A Woelke, Stefan Trela, Kyle LaPak, Lianbo Yu, Joseph McElroy, Thomas J Rosol, Reena Shakya, Thomas Ludwig, Gregory B Lesinski, Soledad A Fernandez, Stephen F Konieczny, Gustavo Leone, Jinghai Wu, Michael C Ostrowski
Preclinical studies have suggested that the pancreatic tumor microenvironment both inhibits and promotes tumor development and growth. Here we establish the role of stromal fibroblasts during acinar-to-ductal metaplasia (ADM), an initiating event in pancreatic cancer formation. The transcription factor V-Ets avian erythroblastosis virus E26 oncogene homolog 2 (ETS2) was elevated in smooth muscle actin-positive fibroblasts in the stroma of pancreatic ductal adenocarcinoma (PDAC) patient tissue samples relative to normal pancreatic controls...
September 2016: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/27639167/hes1-controls-exocrine-cell-plasticity-and-restricts-development-of-pancreatic-ductal-adenocarcinoma-in-a-mouse-model
#14
Ana Hidalgo-Sastre, Roxanne L Brodylo, Clara Lubeseder-Martellato, Bence Sipos, Katja Steiger, Marcel Lee, Guido von Figura, Barbara Grünwald, Suyang Zhong, Marija Trajkovic-Arsic, Florian Neff, Roland M Schmid, Jens T Siveke
Perturbation of the pancreatic acinar cell state can lead to acinar-to-ductal metaplasia (ADM), which is a precursor lesion to the development of pancreatic ductal adenocarcinoma (PDAC). In the pancreas, Notch signaling is active both during development and in adult cellular differentiation processes. Hes1, a key downstream target of the Notch signaling pathway, is expressed in the centroacinar compartment of the adult pancreas as well as in both preneoplastic and malignant lesions. In this study, we used a murine genetic in vivo approach to ablate Hes1 in pancreatic progenitor cells (Ptf1a(+/Cre); Hes1(fl/fl))...
September 14, 2016: American Journal of Pathology
https://www.readbyqxmd.com/read/27633013/genetic-ablation-of-smoothened-in-pancreatic-fibroblasts-increases-acinar-ductal-metaplasia
#15
Xin Liu, Jason R Pitarresi, Maria C Cuitiño, Raleigh D Kladney, Sarah A Woelke, Gina M Sizemore, Sunayana G Nayak, Onur Egriboz, Patrick G Schweickert, Lianbo Yu, Stefan Trela, Daniel J Schilling, Shannon K Halloran, Maokun Li, Shourik Dutta, Soledad A Fernandez, Thomas J Rosol, Gregory B Lesinski, Reena Shakya, Thomas Ludwig, Stephen F Konieczny, Gustavo Leone, Jinghai Wu, Michael C Ostrowski
The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model increased ADM. Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfa) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM...
September 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27630945/minor-salivary-gland-changes-in-oral-epithelial-dysplasia-and-oral-squamous-cell-carcinoma-a-histopathological-study
#16
Sunil Paramel Mohan, Ravi Teja Chitturi, Yoithapprabhunath Thukanayakanpalayam Ragunathan, Suman Jhansi Lakshmi, Jaisanghar Nallusamy, Isaac Joseph
INTRODUCTION: The most common etiology for Oral Squamous Cell Carcinoma (OSCC) is tobacco and tobacco related products which cause nuclear damage to the keratinocytes. The chemical carcinogens not only affect the lining of oral epithelium but also affect the lining epithelium of the excretory ducts of the salivary glands. Thus, there is a possibility of epithelial dysplasia of the salivary duct epithelium which may lead to potential malignant transformation. AIM: The study was performed to see the changes in the minor salivary glands and excretory ducts in cases of oral epithelial dysplasia and OSCC...
July 2016: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/27610015/therapeutic-potential-of-targeting-acinar-cell-reprogramming-in-pancreatic-cancer
#17
REVIEW
Chi-Hin Wong, You-Jia Li, Yang-Chao Chen
Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRas(G12D) mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC...
August 21, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27555909/analysis-of-axin2-expression-and-function-in-murine-models-for-pancreatic-cancer
#18
Dietmar Zechner, Tim Kroemer, Ann-Christin Albert, Maria Schönrogge, Tobias Radecke, Brigitte Vollmar
BACKGROUND: The involvement of Wnt in carcinogenesis and progression of pancreatic cancer is currently intensely discussed. We evaluated activation of the Wnt signaling pathway by using a Wnt reporter mouse strain expressing β-galactosidase under the control of the Axin2 promotor during pancreatitis induced formation of precancerous lesions. We also evaluated activation of Wnt signaling during interaction of pancreatic cancer with the tumor stroma. RESULTS: Activation of Wnt signaling was observed during acinar-to-ductal metaplasia after chronic as well as acute pancreatitis...
2016: Cell & Bioscience
https://www.readbyqxmd.com/read/27514475/legumain-is-activated-in-macrophages-during-pancreatitis
#19
Laura E Edgington-Mitchell, Thomas Wartmann, Alicia K Fleming, Vasilena Gocheva, Wouter A van der Linden, Nimali P Withana, Martijn Verdoes, Luigi Aurelio, Daniel Edgington-Mitchell, TinaMarie Lieu, Belinda S Parker, Bim Graham, Thomas Reinheckel, John B Furness, Johanna A Joyce, Peter Storz, Walter Halangk, Matthew Bogyo, Nigel W Bunnett
Pancreatitis is an inflammatory disease of the pancreas characterized by dysregulated activity of digestive enzymes, necrosis, immune infiltration, and pain. Repeated incidence of pancreatitis is an important risk factor for pancreatic cancer. Legumain, a lysosomal cysteine protease, has been linked to inflammatory diseases such as atherosclerosis, stroke, and cancer. Until now, legumain activation has not been studied during pancreatitis. We used a fluorescently quenched activity-based probe to assess legumain activation during caerulein-induced pancreatitis in mice...
September 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/27485764/tgf-%C3%AE-1-promotes-acinar-to-ductal-metaplasia-of-human-pancreatic-acinar-cells
#20
Jun Liu, Naoki Akanuma, Chengyang Liu, Ali Naji, Glenn A Halff, William K Washburn, Luzhe Sun, Pei Wang
Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species...
2016: Scientific Reports
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