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Pancreatic Neoplasms: HELP
Articles by Ivonne Regel
Based on 12 articles published since 2009
(Why 12 articles?)
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Between 2009 and 2019, Ivonne Regel wrote the following 12 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Pathobiology of pancreatic cancer: implications on therapy. 2016

Regel, Ivonne / Hausmann, Simone / Benitz, Simone / Esposito, Irene / Kleeff, Jörg. ·a Institute of Pathology , Heinrich-Heine-University , Duesseldorf , Germany. · b Department of Surgery , Technical University , Munich , Germany. · c Department of Surgery , The Royal Liverpool and Broadgreen University Hospitals , Liverpool , UK. · d Department of Surgery , Heinrich-Heine-University , Duesseldorf , Germany. ·Expert Rev Anticancer Ther · Pubmed #26652651.

ABSTRACT: Although the concept of tumor heterogeneity was established several decades ago, the interest in this topic is still unbroken. With the identification of inter- and intratumoral genomic rearrangements and the detection of cancer stem cells (CSCs) through phenotypic variations of cancer cells there are increasing options for pancreatic cancer therapy. Indeed, some pre-clinical studies have shown promising results in the treatment of drug-resistant CSCs, whereby a few strategies were already tested in clinical trials. Basically, CSCs are influenced by the tumor microenvironment and an epigenetic reprogramming to gain stem cell-like characteristics. Targeting options inhibiting the epithelial-mesenchymal crosstalk or promoting epigenetic-driven differentiation of CSCs to a less aggressive phenotype raised the possibilities of further therapeutic applications, which will be discussed in this review.

2 Review Energy metabolism and proliferation in pancreatic carcinogenesis. 2012

Regel, Ivonne / Kong, Bo / Raulefs, Susanne / Erkan, Mert / Michalski, Christoph W / Hartel, Mark / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany. ·Langenbecks Arch Surg · Pubmed #22430298.

ABSTRACT: INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer entity with a high proliferative potential. Uncontrolled cell proliferation is mediated by a number of core signaling pathways. Recently, novel data of PDAC biology suggest that these core signal pathways affect cell proliferation and metabolism simultaneously. METHODS: Here, we reviewed the literature on core metabolic signaling pathways in pancreatic carcinogenesis. RESULTS: Results obtained from mouse genetics and in vitro experiments have demonstrated the significance of the Kras, p53, c-Myc, and Lkb1 networks in the proliferation of pancreatic epithelial and cancer cells. At the same time, these major pathways also affect energy metabolism by influencing glucose and glutamine utilization. In particular, Kras-mediated metabolic changes seem to be directly involved in carcinogenesis. However, there is a lack of solid evidence on how metabolism and proliferation are connected in pancreatic carcinogenesis. CONCLUSION: Understanding early and subtle changes in cellular metabolism of pancreatic epithelial-and specifically of acinar-cells, which accompany or directly influence malignant transformation and uncontrolled proliferation, will be paramount to define novel imaging and other modalities for earlier detection of PDAC.

3 Article Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis. 2019

Benitz, Simone / Straub, Tobias / Mahajan, Ujjwal Mukund / Mutter, Jurik / Czemmel, Stefan / Unruh, Tatjana / Wingerath, Britta / Deubler, Sabrina / Fahr, Lisa / Cheng, Tao / Nahnsen, Sven / Bruns, Philipp / Kong, Bo / Raulefs, Susanne / Ceyhan, Güralp O / Mayerle, Julia / Steiger, Katja / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W / Regel, Ivonne. ·Department of Medicine II, University Hospital, LMU Munich, Munich, Germany. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA. · Bioinformatic Unit, Biomedical Center, Faculty of Medicine, LMU Munich, Munich, Germany. · Quantitative Biology Center, University of Tuebingen, Tuebingen, Germany. · Institute of Pathology, Heinrich-Heine University and University Hospital, Duesseldorf, Germany. · Department of Surgery, Technical University Munich, Munich, Germany. · Institute of Pathology, Technical University Munich, Munich, Germany. · Institute of Pathology, Heinrich-Heine-Universitat Dusseldorf, Dusseldorf, Germany. · Department of Surgery, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany. ·Gut · Pubmed #30954952.

ABSTRACT: BACKGROUND AND AIMS: Besides well-defined genetic alterations, the dedifferentiation of mature acinar cells is an important prerequisite for pancreatic carcinogenesis. Acinar-specific genes controlling cell homeostasis are extensively downregulated during cancer development; however, the underlying mechanisms are poorly understood. Now, we devised a novel in vitro strategy to determine genome-wide dynamics in the epigenetic landscape in pancreatic carcinogenesis. DESIGN: With our in vitro carcinogenic sequence, we performed global gene expression analysis and ChIP sequencing for the histone modifications H3K4me3, H3K27me3 and H2AK119ub. Followed by a comprehensive bioinformatic approach, we captured gene clusters with extensive epigenetic and transcriptional remodelling. Relevance of Ring1b-catalysed H2AK119ub in acinar cell reprogramming was studied in an inducible Ring1b knockout mouse model. CRISPR/Cas9-mediated Ring1b ablation as well as drug-induced Ring1b inhibition were functionally characterised in pancreatic cancer cells. RESULTS: The epigenome is vigorously modified during pancreatic carcinogenesis, defining cellular identity. Particularly, regulatory acinar cell transcription factors are epigenetically silenced by the Ring1b-catalysed histone modification H2AK119ub in acinar-to-ductal metaplasia and pancreatic cancer cells. Ring1b knockout mice showed greatly impaired acinar cell dedifferentiation and pancreatic tumour formation due to a retained expression of acinar differentiation genes. Depletion or drug-induced inhibition of Ring1b promoted tumour cell reprogramming towards a less aggressive phenotype. CONCLUSIONS: Our data provide substantial evidence that the epigenetic silencing of acinar cell fate genes is a mandatory event in the development and progression of pancreatic cancer. Targeting the epigenetic repressor Ring1b could offer new therapeutic options.

4 Article Immune Cell and Stromal Signature Associated With Progression-Free Survival of Patients With Resected Pancreatic Ductal Adenocarcinoma. 2018

Mahajan, Ujjwal Mukund / Langhoff, Eno / Goni, Elisabetta / Costello, Eithne / Greenhalf, William / Halloran, Christopher / Ormanns, Steffen / Kruger, Stephan / Boeck, Stefan / Ribback, Silvia / Beyer, Georg / Dombroswki, Frank / Weiss, Frank-Ulrich / Neoptolemos, John P / Werner, Jens / D'Haese, Jan G / Bazhin, Alexandr / Peterhansl, Julian / Pichlmeier, Svenja / Büchler, Markus W / Kleeff, Jörg / Ganeh, Paula / Sendler, Matthias / Palmer, Daniel H / Kohlmann, Thomas / Rad, Roland / Regel, Ivonne / Lerch, Markus M / Mayerle, Julia. ·Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. · Department of Medicine III, University Hospital, LMU Munich, Germany. · Department of Pathology, University Medicine Greifswald, Greifswald, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther University Halle-Wittenberg, Halle, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. · Department of Community Medicine, University Medicine Greifswald, Greifswald, Germany. · Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. Electronic address: julia.mayerle@med.uni-muenchen.de. ·Gastroenterology · Pubmed #30092175.

ABSTRACT: BACKGROUND & AIMS: Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS: We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS. Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort. RESULTS: Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of -0.32 (95% confidence interval [CI] -0.35 to -0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050-0.32); we called these patterns histologic signatures. Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64-0.83; accuracy P < .001). CONCLUSIONS: In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.

5 Article Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy. 2018

Kong, Bo / Bruns, Philipp / Behler, Nora A / Chang, Ligong / Schlitter, Anna Melissa / Cao, Jing / Gewies, Andreas / Ruland, Jürgen / Fritzsche, Sina / Valkovskaya, Nataliya / Jian, Ziying / Regel, Ivonne / Raulefs, Susanne / Irmler, Martin / Beckers, Johannes / Friess, Helmut / Erkan, Mert / Mueller, Nikola S / Roth, Susanne / Hackert, Thilo / Esposito, Irene / Theis, Fabian J / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China. · Institute of Computational Biology, Helmholtz-Zentrum München GmbH, Neuherberg, Germany. · Institute of Pathology, TUM, Munich, Germany. · Institute für Klinische Chemie und Pathobiochemie, TUM, Munich, Germany. · Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany. · German Cancer Consortium (DKTK) at the partner site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany. · German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany. · Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany. · Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany. · Chair of Experimental Genetics, Technische Universität München, Freising, Germany. · Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany. · Department of Surgery, Koc University, Istanbul, Turkey. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Mathematics, TUM, Munich, Germany. · NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. ·Gut · Pubmed #27646934.

ABSTRACT: OBJECTIVE: The initial steps of pancreatic regeneration versus carcinogenesis are insufficiently understood. Although a combination of oncogenic Kras and inflammation has been shown to induce malignancy, molecular networks of early carcinogenesis remain poorly defined. DESIGN: We compared early events during inflammation, regeneration and carcinogenesis on histological and transcriptional levels with a high temporal resolution using a well-established mouse model of pancreatitis and of inflammation-accelerated Kras RESULTS: We defined three distinctive phases-termed inflammation, regeneration and refinement-following induction of moderate acute pancreatitis in wild-type mice. These corresponded to different waves of proliferation of mesenchymal, progenitor-like and acinar cells. Pancreas regeneration required a coordinated transition of proliferation between progenitor-like and acinar cells. In mice harbouring an oncogenic Kras mutation and challenged with pancreatitis, there was an extended inflammatory phase and a parallel, continuous proliferation of mesenchymal, progenitor-like and acinar cells. Analysis of high-resolution transcriptional data from wild-type animals revealed that organ regeneration relied on a complex interaction of a gene network that normally governs acinar cell homeostasis, exocrine specification and intercellular signalling. In mice with oncogenic Kras, a specific carcinogenic signature was found, which was preserved in full-blown mouse pancreas cancer. CONCLUSIONS: These data define a transcriptional signature of early pancreatic carcinogenesis and a molecular network driving formation of preneoplastic lesions, which allows for more targeted biomarker development in order to detect cancer earlier in patients with pancreatitis.

6 Article Molecular, morphological and survival analysis of 177 resected pancreatic ductal adenocarcinomas (PDACs): Identification of prognostic subtypes. 2017

Schlitter, Anna Melissa / Segler, Angela / Steiger, Katja / Michalski, Christoph W / Jäger, Carsten / Konukiewitz, Björn / Pfarr, Nicole / Endris, Volker / Bettstetter, Markus / Kong, Bo / Regel, Ivonne / Kleeff, Jörg / Klöppel, Günter / Esposito, Irene. ·Institute of Pathology, Technische Universität München, Munich, Germany. · Department of Surgery, University Hospital Heidelberg, Germany. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany. · Molecular Pathology South-Bavaria, Munich, Germany. · Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany. · The Royal Liverpool and Broadgreen University Hospitals, Prescot Street, Liverpool L7 8XP, United Kingdom. · Department of General-, Visceral- and Pediatric Surgery, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany. ·Sci Rep · Pubmed #28145465.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has generally a poor prognosis, but recent data suggest that there are molecular subtypes differing in clinical outcome. This study examines the association between histopathologic heterogeneity, genetic profile, and survival. Tumor histology from 177 resected PDAC patients with follow-up data was subclassified according to predominant growth pattern, and four key genes were analyzed. PDACs were classified as conventional (51%), combined with a predominant component (41%), variants and special carcinomas (8%). Patients with combined PDACs and a dominant cribriform component survived longer than patients with conventional or other combined PDACs. Genetic alterations in at least two out of four genes were found in 95% of the patients (KRAS 93%, TP53 79%, CDKN2A/p16 75%, SMAD4 37%). Patients with less than four mutations survived significantly longer (p = 0.04) than those with alterations in all four genes. Patients with either wildtype KRAS or CDKN2A/p16 lived significantly longer than those with alterations in these genes (p = 0.018 and p = 0.006, respectively). Our data suggest that the number of altered genes, the mutational status of KRAS and certain morphological subtypes correlate with the outcome of patients with PDAC. Future pathology reporting of PDAC should therefore include the KRAS status and a detailed morphological description.

7 Article Polycomb repressor complex 1 promotes gene silencing through H2AK119 mono-ubiquitination in acinar-to-ductal metaplasia and pancreatic cancer cells. 2016

Benitz, Simone / Regel, Ivonne / Reinhard, Tobias / Popp, Anna / Schäffer, Isabell / Raulefs, Susanne / Kong, Bo / Esposito, Irene / Michalski, Christoph W / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Munich, Germany. · Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. · The Royal Liverpool and Broadgreen University Hospitals, Liverpool, United Kingdom. · Department of Surgery, Heinrich-Heine University, Duesseldorf, Germany. ·Oncotarget · Pubmed #26716510.

ABSTRACT: Acinar-to-ductal metaplasia (ADM) occurring in cerulein-mediated pancreatitis or in oncogenic Kras-driven pancreatic cancer development is accompanied by extensive changes in the transcriptional program. In this process, acinar cells shut down the expression of acinar specific differentiation genes and re-express genes usually found in embryonic pancreatic progenitor cells. Previous studies have demonstrated that a loss of acinar-specific transcription factors sensitizes the cells towards oncogenic transformation, ultimately resulting in cancer development. However, the mechanism behind the transcriptional silencing of acinar cell fate genes in ADM and pancreatic cancer is largely unknown. Here, we analyzed whether elevated levels of the polycomb repressor complex 1 (PRC1) components Bmi1 and Ring1b and their catalyzed histone modification H2AK119ub in ADMs and tumor cells, are responsible for the mediation of acinar gene silencing. Therefore, we performed chromatin-immunoprecipitation in in vitro generated ADMs and isolated murine tumor cells against the repressive histone modifications H3K27me3 and H2AK119ub. We established that the acinar transcription factor complex Ptf1-L is epigenetically silenced in ADMs as well as in pancreatic tumor cells. For the first time, this work presents a possible mechanism of acinar gene silencing, which is an important prerequisite in the initiation and maintenance of a dedifferentiated cell state in ADMs and tumor cells.

8 Article A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling. 2016

Kong, Bo / Wu, Weiwei / Cheng, Tao / Schlitter, Anna Melissa / Qian, Chengjia / Bruns, Philipp / Jian, Ziying / Jäger, Carsten / Regel, Ivonne / Raulefs, Susanne / Behler, Nora / Irmler, Martin / Beckers, Johannes / Friess, Helmut / Erkan, Mert / Siveke, Jens T / Tannapfel, Andrea / Hahn, Stephan A / Theis, Fabian J / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · Department of Surgery, Technische Universität München (TUM), Munich, Germany Institute of Computational Biology, Helmholtz-Zentrum München, Munich, Germany. · Institute of Experimental Genetics (IEG), Helmholtz-Zentrum München, Munich, Germany. · Institute of Experimental Genetics (IEG), Helmholtz-Zentrum München, Munich, Germany Technische Universität München, Chair of Experimental Genetics, Freising, Germany Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Germany. · Department of Surgery, Koc University School of Medicine, Istanbul, Turkey. · Department of Gastroenterology, TUM, Munich, Germany. · Institute of Pathology, Ruhr-University Bochum, Bochum, Germany. · Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany. · Institute of Computational Biology, Helmholtz-Zentrum München, Munich, Germany. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·Gut · Pubmed #25601637.

ABSTRACT: OBJECTIVE: Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity. DESIGN: We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material. RESULTS: Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype. CONCLUSIONS: These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.

9 Article Pancreas-specific activation of mTOR and loss of p53 induce tumors reminiscent of acinar cell carcinoma. 2015

Kong, Bo / Cheng, Tao / Qian, Chengjia / Wu, Weiwei / Steiger, Katja / Cao, Jing / Schlitter, Anna Melissa / Regel, Ivonne / Raulefs, Susanne / Friess, Helmut / Erkan, Mert / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · Department of Surgery, Koc School of Medicine, Istanbul, Turkey. · Institute of Pathology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany. · Royal Liverpool and Broadgreen University Hospitals, Liverpool, UK. · Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. cwmichalski@gmail.com. ·Mol Cancer · Pubmed #26683340.

ABSTRACT: BACKGROUND: Pancreatic acinar cell carcinoma (ACC) is a rare tumor entity with an unfavorable prognosis. Recent whole-exome sequencing identified p53 mutations in a subset of human ACC. Activation of the mammalian target of rapamycin (mTOR) pathway is associated with various pancreatic neoplasms. We thus aimed at analyzing whether activation of mTOR with a concomitant loss of p53 may initiate ACC. METHODS: We generated transgenic mouse models in which mTOR was hyperactivated through pancreas-specific, homozygous tuberous sclerosis 1 (Tsc1) deficiency, with or without deletion of p53 (Tsc1 (-/-) and Tsc1 (-/-) ; p53 (-/-) ). Activity of mTOR signaling was investigated using mouse tissues and isolated murine cell lines. Human ACC specimens were used to corroborate the findings from the transgenic mouse models. RESULTS: Hyperactive mTOR signaling in Tsc1 (-/-) mice was not oncogenic but rather induced a near-complete loss of the pancreatic acinar compartment. Acinar cells were lost as a result of apoptosis which was associated with p53 activation. Concomitantly, ductal cells were enriched. Ablation of p53 in Tsc1-deficient mice prevented acinar cell death but promoted formation of acinar cells with severe nuclear abnormalities. One out of seven Tsc1 (-/-) ; p53 (-/-) animals developed pancreatic tumors showing a distinctive tumor morphology, reminiscent of human ACC. Hyperactive mTOR signaling was also detected in a subset of human ACC. CONCLUSION: Hyperactive mTOR signaling combined with loss of p53 in mice induces tumors similar to human ACC.

10 Article Hypoxia-induced endoplasmic reticulum stress characterizes a necrotic phenotype of pancreatic cancer. 2015

Kong, Bo / Cheng, Tao / Wu, Weiwei / Regel, Ivonne / Raulefs, Susanne / Friess, Helmut / Erkan, Mert / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Department of Surgery, Koc University School of Medicine, Istanbul, Turkey. · Institute of Pathology, Medical University Innsbruck, Innsbruck, Austria. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·Oncotarget · Pubmed #26452217.

ABSTRACT: Stromal fibrosis and tissue necrosis are major histological sequelae of hypoxia. The hypoxia-to-fibrosis sequence is well-documented in pancreatic ductal adenocarcinoma (PDAC). However, hypoxic and necrotic PDAC phenotypes are insufficiently characterized. Recently, reduction of tuberous sclerosis expression in mice together with oncogenic Kras demonstrated a rapidly metastasizing phenotype with histologically eccentric necrosis, transitional hypoxia and devascularisation. We established cell lines from these tumors and transplanted them orthotopically into wild-type mice to test their abilities to recapitulate the histological features of the primary lesions. Notably, the necrotic phenotype was reproduced by only a subset of cell lines while others gave rise to dedifferentiated tumors with significantly reduced necrosis. In vitro analysis of the necrotic tumor-inducing cell lines revealed that these cells released a significant amount of vascular endothelial growth factor A (Vegfa). However, its release was not further increased under hypoxic conditions. Defective hypoxia-induced Vegfa secretion was not due to impaired Vegfa transcription or hypoxia-inducible factor 1-alpha activation, but rather a result of hypoxia-induced endoplasmic reticulum (ER) stress. We thus identified hypoxia-induced ER stress as an important pathway in PDACs with tissue necrosis and rapid metastasis.

11 Article Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer. 2015

Müller, Sören / Raulefs, Susanne / Bruns, Philipp / Afonso-Grunz, Fabian / Plötner, Anne / Thermann, Rolf / Jäger, Carsten / Schlitter, Anna Melissa / Kong, Bo / Regel, Ivonne / Roth, W Kurt / Rotter, Björn / Hoffmeier, Klaus / Kahl, Günter / Koch, Ina / Theis, Fabian J / Kleeff, Jörg / Winter, Peter / Michalski, Christoph W. ·Molecular BioSciences, Goethe University, Frankfurt am Main, Germany. s.mueller@bio.uni-frankfurt.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. s.mueller@bio.uni-frankfurt.de. · Molecular Bioinformatics Group, Institute of Computer Science, Cluster of Excellence Frankfurt 'Macromolecular Complexes' Faculty of Computer Science and Mathematics, Frankfurt am Main, Germany. s.mueller@bio.uni-frankfurt.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. susanne.raulefs@tum.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. philipp.bruns@helmholtz-muenchen.de. · Molecular BioSciences, Goethe University, Frankfurt am Main, Germany. fgrunz@stud.uni-frankfurt.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. fgrunz@stud.uni-frankfurt.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. ploetner@genxpro.de. · GFE Blut mbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. rolf.thermann@gfeblut.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. Carsten.Jaeger@lrz.tu-muenchen.de. · Department of Pathology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. melissa.schlitter@lrz.tu-muenchen.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. kongbo81@hotmail.com. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. ivonne.regel@lrz.tum.de. · GFE Blut mbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. kurt.roth@gfeblut.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. rotter@genxpro.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. hoffmeier@genxpro.de. · Molecular BioSciences, Goethe University, Frankfurt am Main, Germany. kahl@em.uni-frankfurt.de. · Molecular Bioinformatics Group, Institute of Computer Science, Cluster of Excellence Frankfurt 'Macromolecular Complexes' Faculty of Computer Science and Mathematics, Frankfurt am Main, Germany. ina.koch@bioinformatik.uni-frankfurt.de. · Institute of Computational Biology, Helmholtz Zentrum Munich, Neuherberg, Germany. fabian.theis@helmholtz-muenchen.de. · Department of Mathematics, TU Munich, Boltzmannstrasse 3, Garching, Germany. fabian.theis@helmholtz-muenchen.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. kleeff@tum.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. pwinter@genxpro.de. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. cwmichalski@gmail.com. ·Mol Cancer · Pubmed #25910082.

ABSTRACT: BACKGROUND: Previous studies identified microRNAs (miRNAs) and messenger RNAs with significantly different expression between normal pancreas and pancreatic cancer (PDAC) tissues. Due to technological limitations of microarrays and real-time PCR systems these studies focused on a fixed set of targets. Expression of other RNA classes such as long intergenic non-coding RNAs or sno-derived RNAs has rarely been examined in pancreatic cancer. Here, we analysed the coding and non-coding transcriptome of six PDAC and five control tissues using next-generation sequencing. RESULTS: Besides the confirmation of several deregulated mRNAs and miRNAs, miRNAs without previous implication in PDAC were detected: miR-802, miR-2114 or miR-561. SnoRNA-derived RNAs (e.g. sno-HBII-296B) and piR-017061, a piwi-interacting RNA, were found to be differentially expressed between PDAC and control tissues. In silico target analysis of miR-802 revealed potential binding sites in the 3' UTR of TCF4, encoding a transcription factor that controls Wnt signalling genes. Overexpression of miR-802 in MiaPaCa pancreatic cancer cells reduced TCF4 protein levels. Using Massive Analysis of cDNA Ends (MACE) we identified differential expression of 43 lincRNAs, long intergenic non-coding RNAs, e.g. LINC00261 and LINC00152 as well as several natural antisense transcripts like HNF1A-AS1 and AFAP1-AS1. Differential expression was confirmed by qPCR on the mRNA/miRNA/lincRNA level and by immunohistochemistry on the protein level. CONCLUSIONS: Here, we report a novel lncRNA, sncRNA and mRNA signature of PDAC. In silico prediction of ncRNA targets allowed for assigning potential functions to differentially regulated RNAs.

12 Article RSPO2 Enhances Canonical Wnt Signaling to Confer Stemness-Associated Traits to Susceptible Pancreatic Cancer Cells. 2015

Ilmer, Matthias / Boiles, Alejandro Recio / Regel, Ivonne / Yokoi, Kenji / Michalski, Christoph W / Wistuba, Ignacio I / Rodriguez, Jaime / Alt, Eckhard / Vykoukal, Jody. ·Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. matthias.ilmer@googlemail.com jody@mdanderson.org. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Surgery, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Medicine, Tulane University Health Science Center, New Orleans, Lousiana. ·Cancer Res · Pubmed #25769727.

ABSTRACT: Cancer stem cells (CSC) present a formidable clinical challenge by escaping therapeutic intervention and seeding tumors through processes that remain incompletely understood. Here, we describe small subpopulations of pancreatic cancer cells with high intrinsic Wnt activity (Wnt(high)) that possess properties indicative of CSCs, including drug resistance and tumor-initiating capacity, whereas cell populations with negligible Wnt activity (Wnt(low)) preferentially express markers of differentiation. Spontaneous response to extrinsic Wnt signals induces signaling networks comprising ERK1/2 and epithelial-mesenchymal transition that subsequently confer cancer stemness traits to susceptible cells. Wnt enhancer R-Spondin 2 (RSPO2) seems to play a prominent upstream role in regulating this interplay. In this context, Wnt(high) cells were more likely to give rise to Wnt(high) progeny, tended to be more metastatic, and revealed higher levels of RSPO2 expression. Our studies reveal adaptive aspects of pancreatic cancer stemness arising from driver populations of CSCs that misappropriate functional and responsive elements of archetypical self-renewal pathways. Blocking such stemness-promoting pathways in conjunction with established chemotherapy could provide means to disrupt dynamic CSC process and present novel therapeutic targets and strategies.