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Pancreatic Neoplasms: HELP
Articles by Katja Steiger
Based on 28 articles published since 2010
(Why 28 articles?)
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Between 2010 and 2020, K. Steiger wrote the following 28 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Pathology, genetics and precursors of human and experimental pancreatic neoplasms: An update. 2015

Esposito, Irene / Segler, Angela / Steiger, Katja / Klöppel, Günter. ·Institute of Pathology, Heinrich-Heine-University of Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany. Electronic address: Irene.Esposito@med.uni-duesseldorf.de. · Institute of Pathology, Technische Universität München, Ismaningerstr. 22, 81675, Munich, Germany. ·Pancreatology · Pubmed #26365060.

ABSTRACT: Over the past decade, there have been substantial improvements in our knowledge of pancreatic neoplasms and their precursor lesions. Extensive genetic analyses, recently using high-throughput molecular techniques and next-generation sequencing methodologies, and the development of sophisticated genetically engineered mouse models closely recapitulating human disease, have improved our understanding of the genetic basis of pancreatic neoplasms. These advances are paving the way for refined, molecular-based classifications of pancreatic neoplasms with the potential to better predict prognosis and, possibly, response to therapy. Another major development resides in the identification of subsets of pancreatic exocrine and endocrine neoplasms which occur in the context of hereditary syndromes and whose genetic basis and tumor development have been at least partially defined. However, despite all molecular progress, correct and careful morphological characterization of tissue specimens both in the context of experimental and routine diagnostic pathology represents the basis for any further genetic investigation or clinical decision. This review focuses on the current and new concepts of classification and on the current models of tumor development, both in the field of exocrine and endocrine neoplasms, and underscores the importance of applying standardized terminology to allow adequate data interpretation and promote scientific exchange in the field of pancreas research.

2 Article Image-Based Molecular Phenotyping of Pancreatic Ductal Adenocarcinoma. 2020

Kaissis, Georgios A / Ziegelmayer, Sebastian / Lohöfer, Fabian K / Harder, Felix N / Jungmann, Friederike / Sasse, Daniel / Muckenhuber, Alexander / Yen, Hsi-Yu / Steiger, Katja / Siveke, Jens / Friess, Helmut / Schmid, Roland / Weichert, Wilko / Makowski, Marcus R / Braren, Rickmer F. ·Technical University of Munich, School of Medicine, Department of Diagnostic and Interventional Radiology, 81675 Munich, Germany. · Imperial College of Science, Technology and Medicine, Faculty of Engineering, Department of Computing, SW7 2AZ London, UK. · Technical University of Munich, School of Medicine, Institute for Pathology, 81675 Munich, Germany. · Institute of Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, 45147 Essen, Germany. · Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, parter site Essen, Germany) and German Cancer Research Center, DKFZ, 69120 Heidelberg, Germany. · Technical University of Munich, School of Medicine, Surgical Clinic and Policlinic, 81675 Munich, Germany. · Technical University of Munich, School of Medicine, Department of Internal Medicine II, 81675 Munich, Germany. ·J Clin Med · Pubmed #32155990.

ABSTRACT: To bridge the translational gap between recent discoveries of distinct molecular phenotypes of pancreatic cancer and tangible improvements in patient outcome, there is an urgent need to develop strategies and tools informing and improving the clinical decision process. Radiomics and machine learning approaches can offer non-invasive whole tumor analytics for clinical imaging data-based classification. The retrospective study assessed baseline computed tomography (CT) from 207 patients with proven pancreatic ductal adenocarcinoma (PDAC). Following expert level manual annotation, Pyradiomics was used for the extraction of 1474 radiomic features. The molecular tumor subtype was defined by immunohistochemical staining for KRT81 and HNF1a as quasi-mesenchymal (QM) vs. non-quasi-mesenchymal (non-QM). A Random Forest machine learning algorithm was developed to predict the molecular subtype from the radiomic features. The algorithm was then applied to an independent cohort of histopathologically unclassifiable tumors with distinct clinical outcomes. The classification algorithm achieved a sensitivity, specificity and ROC-AUC (area under the receiver operating characteristic curve) of 0.84 ± 0.05, 0.92 ± 0.01 and 0.93 ± 0.01, respectively. The median overall survival for predicted QM and non-QM tumors was 16.1 and 20.9 months, respectively, log-rank-test

3 Article SUMO pathway inhibition targets an aggressive pancreatic cancer subtype. 2020

Biederstädt, Alexander / Hassan, Zonera / Schneeweis, Christian / Schick, Markus / Schneider, Lara / Muckenhuber, Alexander / Hong, Yingfen / Siegers, Gerrit / Nilsson, Lisa / Wirth, Matthias / Dantes, Zahra / Steiger, Katja / Schunck, Kathrin / Langston, Steve / Lenhof, H-P / Coluccio, Andrea / Orben, Felix / Slawska, Jolanta / Scherger, Anna / Saur, Dieter / Müller, Stefan / Rad, Roland / Weichert, Wilko / Nilsson, Jonas / Reichert, Maximilian / Schneider, Günter / Keller, Ulrich. ·Medical Clinic and Policlinic III, Klinikum rechts der Isar, Technical University Munich, München, Germany. · Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, München, Germany. · Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany. · Center for Bioinformatics, Saarland Informatics Campus, Saarland University, Saarbrücken, Germany. · Saarbrücken Graduate School of Computer Science, Saarland Informatics Campus, Saarland University, Saarbrücken, Germany. · Institute of Pathology, Technical University Munich, München, Germany. · Department of Surgery, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. · Goethe University, Medical School, Institute of Biochemistry II, Frankfurt, Germany. · Oncology Drug Discovery Unit, Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA. · Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, München, Germany. · Institute of Molecular Oncology and Functional Genomics, Technical University Munich, München, Germany. · Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, München, Germany guenter.schneider@tum.de ulrich.keller@charite.de. · Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany guenter.schneider@tum.de ulrich.keller@charite.de. ·Gut · Pubmed #32001555.

ABSTRACT: OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies. DESIGN: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC. RESULTS: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. CONCLUSION: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.

4 Article A machine learning algorithm predicts molecular subtypes in pancreatic ductal adenocarcinoma with differential response to gemcitabine-based versus FOLFIRINOX chemotherapy. 2019

Kaissis, Georgios / Ziegelmayer, Sebastian / Lohöfer, Fabian / Steiger, Katja / Algül, Hana / Muckenhuber, Alexander / Yen, Hsi-Yu / Rummeny, Ernst / Friess, Helmut / Schmid, Roland / Weichert, Wilko / Siveke, Jens T / Braren, Rickmer. ·Department of Diagnostic and Interventional Radiology, School of Medicine, Technical University of Munich, Munich, Germany. · Department of Pathology, School of Medicine, Technical University of Munich, Munich, Germany. · Department of Internal Medicine II, School of Medicine, Technical University of Munich, Munich, Germany. · Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany. · Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. ·PLoS One · Pubmed #31577805.

ABSTRACT: PURPOSE: Development of a supervised machine-learning model capable of predicting clinically relevant molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) from diffusion-weighted-imaging-derived radiomic features. METHODS: The retrospective observational study assessed 55 surgical PDAC patients. Molecular subtypes were defined by immunohistochemical staining of KRT81. Tumors were manually segmented and 1606 radiomic features were extracted with PyRadiomics. A gradient-boosted-tree algorithm was trained on 70% of the patients (N = 28) and tested on 30% (N = 17) to predict KRT81+ vs. KRT81- tumor subtypes. A gradient-boosted survival regression model was fit to the disease-free and overall survival data. Chemotherapy response and survival were assessed stratified by subtype and radiomic signature. Radiomic feature importance was ranked. RESULTS: The mean±STDEV sensitivity, specificity and ROC-AUC were 0.90±0.07, 0.92±0.11, and 0.93±0.07, respectively. The mean±STDEV concordance indices between the disease-free and overall survival predicted by the model based on the radiomic parameters and actual patient survival were 0.76±0.05 and 0.71±0.06, respectively. Patients with a KRT81+ subtype experienced significantly diminished median overall survival compared to KRT81- patients (7.0 vs. 22.6 months, HR 4.03, log-rank-test P = <0.001) and a significantly improved response to gemcitabine-based chemotherapy over FOLFIRINOX (10.14 vs. 3.8 months median overall survival, HR 2.33, P = 0.037) compared to KRT81- patients, who responded significantly better to FOLFIRINOX over gemcitabine-based treatment (30.8 vs. 13.4 months median overall survival, HR 2.41, P = 0.027). Entropy was ranked as the most important radiomic feature. CONCLUSIONS: The machine-learning based analysis of radiomic features enables the prediction of subtypes of PDAC, which are highly relevant for disease-free and overall patient survival and response to chemotherapy.

5 Article Primary Solid and Cystic Tumours of the Exocrine Pancreas in Cats. 2019

Törner, K / Aupperle-Lellbach, H / Staudacher, A / Staudacher, M / Steiger, K. ·LABOKLIN GmbH & Co. KG, Labor für klinische Diagnostik, Steubenstr. 4, Bad Kissingen, Germany. Electronic address: katrin.toerner@yahoo.de. · LABOKLIN GmbH & Co. KG, Labor für klinische Diagnostik, Steubenstr. 4, Bad Kissingen, Germany. · Tierärztliche Klinik Dr. Staudacher, Trierer Str. 652-658, Aachen, Germany. · Comparative Experimental Pathology, Institut für Pathologie, Technische Universität München, Trogerstrasse 18, Munich, Germany. ·J Comp Pathol · Pubmed #31159950.

ABSTRACT: Tumours of the exocrine pancreas are rare in cats and few cases are described in the literature. Cystic tumours of the pancreas are not included in the World Health Organization (WHO) international histological classification of tumours of domestic animals. The aim of this study was to characterize the pathology of primary epithelial tumours of the feline exocrine pancreas, with emphasis on cystic tumours. We reviewed tumours of the exocrine pancreas in 70 cats, including complete tumours or the entire pancreas (n = 18) and excisional biopsy samples of pancreatic tumours (n = 52). Macroscopically, the tumours were grouped as solid (n = 45) or cystic (n = 25). Solid tumours were subdivided into adenomas (n = 5) and carcinomas (n = 40) and cystic neoplasms into adenomas (n = 15), carcinomas (n = 7) and cases with diverse growth patterns (n = 3). All five grossly solid adenomas had acinar morphology, while the macroscopically solid carcinomas showed acinar (n = 17), tubular (n = 14) or mixed (n = 9) growth microscopically. Cystic adenomas had acinar (n = 2), tubular (n = 12) or mixed (n = 1) growth, while cystic carcinomas had exclusively tubular growth (n = 7). Three cases with cystic lesions showed diverse histopathological growth patterns. The clinical outcome was available in 57 cases. The majority of cats with carcinomas died or were humanely destroyed during or shortly after surgery (n = 32). However, 2/7 animals with cystic carcinomas showed longer survival times. Cats with cystic adenomas had survival times of up to 5 years. The results of this study show that cystic pancreatic tumours should be considered a differential diagnosis in cats with cystic intra-abdominal masses, even though these are not yet described in the WHO classification. Based on the relatively long survival times of cats with cystic adenomas, complete resection with subsequent histopathological examination is recommended.

6 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.

7 Article Ductal obstruction promotes formation of preneoplastic lesions from the pancreatic ductal compartment. 2019

Cheng, Tao / Zhang, Zhiheng / Jian, Ziying / Raulefs, Susanne / Schlitter, Anna Melissa / Steiger, Katja / Maeritz, Nadja / Zhao, Yamin / Shen, Shanshan / Zou, Xiaoping / Ceyhan, Güralp O / Friess, Helmut / Kleeff, Jörg / Michalski, Christoph W / Kong, Bo. ·Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich (TUM), Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · German Cancer Consortium (DKTK) at the partner site Munich, Munich, Germany. · Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle, Germany. ·Int J Cancer · Pubmed #30412288.

ABSTRACT: Pancreatitis is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC). Previous studies in mice have demonstrated that pancreatitis contributes to oncogenic Kras-driven carcinogenesis, probably initiated in acinar cells; however, oncogenic Kras alone or in combination with caerulein-induced pancreatitis is not sufficient in initiating PDAC from the ductal compartment. We thus introduced ductal obstruction - which induces a more severe form of pancreatitis - by pancreatic ductal ligation in mice harbouring oncogenic Kras. This induced a particular phenotype with highly proliferative nonmucinous cells with nuclear atypia. Around these lesions, there was a significant proliferation of activated fibroblasts and infiltration of immune cells, corroborating the pathological features of preneoplastic lesions. Lineage-tracing experiments revealed that these preneoplastic cells derived from two distinctive cellular sources: acinar and ductal cells. Phenotypic characterisation revealed that the duct-derived preneoplastic lesions show a high proliferative potential with persistent activation of tumour-promoting inflammatory pathways while the acinar-derived ones were less proliferative with persistent p53 activation. Furthermore, the duct-derived preneoplastic cells have a particularly high nuclear-to-cytoplasmic ratio. These data demonstrate that ductal obstruction promotes preneoplastic lesion formation from the pancreatic ductal compartment.

8 Article Levels of the Autophagy-Related 5 Protein Affect Progression and Metastasis of Pancreatic Tumors in Mice. 2019

Görgülü, Kivanc / Diakopoulos, Kalliope N / Ai, Jiaoyu / Schoeps, Benjamin / Kabacaoglu, Derya / Karpathaki, Angeliki-Faidra / Ciecielski, Katrin J / Kaya-Aksoy, Ezgi / Ruess, Dietrich A / Berninger, Alexandra / Kowalska, Marlena / Stevanovic, Marija / Wörmann, Sonja M / Wartmann, Thomas / Zhao, Yue / Halangk, Walter / Voronina, Svetlana / Tepikin, Alexey / Schlitter, Anna Melissa / Steiger, Katja / Artati, Anna / Adamski, Jerzy / Aichler, Michaela / Walch, Axel / Jastroch, Martin / Hartleben, Götz / Mantzoros, Christos S / Weichert, Wilko / Schmid, Roland M / Herzig, Stephan / Krüger, Achim / Sainz, Bruno / Lesina, Marina / Algül, Hana. ·Klinik und Poliklinik für Innere Medizin II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Institute of Molecular Immunology and Experimental Oncology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Klinik für Chirurgie Bereich Experimentelle Operative Medizin, Universitätsklinikum Magdeburg, Magdeburg, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Institute of Pathology, Technische Universität München, Munich, Germany and German Cancer Consortium, Munich, Germany. · Institute of Pathology, Technische Universität München, Munich, Germany and German Cancer Consortium, Munich, Germany; Comparative Experimental Pathology, Institute of Pathology, Technische Universität München, Munich, Germany. · Institute of Experimental Genetics, Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany. · Institute of Experimental Genetics, Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany; Institute for Diabetes and Cancer, German Center for Diabetes Research, Neuherberg, Germany; Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany. · Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany. · Helmholtz Diabetes Center and German Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany. · Institute for Diabetes and Cancer, German Center for Diabetes Research, Neuherberg, Germany. · Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts. · Department of Biochemistry, School of Medicine, Autónoma University of Madrid, Madrid, Spain. · Klinik und Poliklinik für Innere Medizin II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. Electronic address: marina.lesina@tum.de. · Klinik und Poliklinik für Innere Medizin II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. Electronic address: hana.alguel@mri.tum.de. ·Gastroenterology · Pubmed #30296435.

ABSTRACT: BACKGROUND AND AIMS: Cells in pancreatic ductal adenocarcinoma (PDAC) undergo autophagy, but its effects vary with tumor stage and genetic factors. We investigated the consequences of varying levels of the autophagy related 5 (Atg5) protein on pancreatic tumor formation and progression. METHODS: We generated mice that express oncogenic Kras in primary pancreatic cancer cells and have homozygous disruption of Atg5 (A5;Kras) or heterozygous disruption of Atg5 (A5 RESULTS: A5 CONCLUSIONS: In mice that express oncogenic Kras in pancreatic cells, heterozygous disruption of Atg5 and reduced protein levels promotes tumor development, whereas homozygous disruption of Atg5 blocks tumorigenesis. Therapeutic strategies to alter autophagy in PDAC should consider the effects of ATG5 levels to avoid the expansion of resistant and highly aggressive cells.

9 Article A Novel Approach for Image-Guided 2019

Schug, Christina / Gupta, Aayush / Urnauer, Sarah / Steiger, Katja / Cheung, Phyllis Fung-Yi / Neander, Christian / Savvatakis, Konstantinos / Schmohl, Kathrin A / Trajkovic-Arsic, Marija / Schwenk, Nathalie / Schwaiger, Markus / Nelson, Peter J / Siveke, Jens T / Spitzweg, Christine. ·Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany. · Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. · Institute of Pathology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. · Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Nuclear Medicine, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. · Clinical Biochemistry Group, Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany. · Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany. Christine.Spitzweg@med.uni-muenchen.de. ·Mol Cancer Res · Pubmed #30224540.

ABSTRACT: The sodium iodide symporter (

10 Article Glycemic Variability Promotes Both Local Invasion and Metastatic Colonization by Pancreatic Ductal Adenocarcinoma. 2018

Jian, Ziying / Cheng, Tao / Zhang, Zhiheng / Raulefs, Susanne / Shi, Kuangyu / Steiger, Katja / Maeritz, Nadja / Kleigrewe, Karin / Hofmann, Thomas / Benitz, Simone / Bruns, Philipp / Lamp, Daniel / Jastroch, Martin / Akkan, Jan / Jäger, Carsten / Huang, Peilin / Nie, Shuang / Shen, Shanshan / Zou, Xiaoping / Ceyhan, Güralp O / Michalski, Christoph W / Friess, Helmut / Kleeff, Jörg / Kong, Bo. ·Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich (TUM), Munich, Germany. · Department of Nuclear Medicine, TUM, Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · Bavarian Center for Biomolecular Mass Spectrometry, Freising, Germany. · Medizinische Klinik und Poliklinik II, Klinikum der LMU, Munich, Germany. · Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany. · Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany. · German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany. · Division of Metabolic Diseases, TUM, Munich, Germany. · Department of Pathology, School of Medicine, Southeast University, Nanjing, China. · Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle, Germany. · German Cancer Consortium (DKTK) at the partner site Munich, Munich, Germany. ·Cell Mol Gastroenterol Hepatol · Pubmed #30258965.

ABSTRACT: Background & Aims: Although nearly half of pancreatic ductal adenocarcinoma (PDAC) patients have diabetes mellitus with episodes of hyperglycemia, its tumor microenvironment is hypoglycemic. Thus, it is crucial for PDAC cells to develop adaptive mechanisms dealing with oscillating glucose levels. So far, the biological impact of such glycemic variability on PDAC biology remains unknown. Methods: Murine PDAC cells were cultured in low- and high-glucose medium to investigate the molecular, biochemical, and metabolic influence of glycemic variability on tumor behavior. A set of in vivo functional assays including orthotopic implantation and portal and tail vein injection were used. Results were further confirmed on tissues from PDAC patients. Results: Glycemic variability has no significant effect on PDAC cell proliferation. Hypoglycemia is associated with local invasion and angiogenesis, whereas hyperglycemia promotes metastatic colonization. Increased metastatic colonization under hyperglycemia is due to increased expression of runt related transcription factor 3 (Runx3), which further activates expression of collagen, type VI, alpha 1 (Col6a1), forming a glycemic pro-metastatic pathway. Through epigenetic machinery, retinoic acid receptor beta (Rarb) expression fluctuates according to glycemic variability, acting as a critical sensor relaying the glycemic signal to Runx3/Col6a1. Moreover, the signal axis of Rarb/Runx3/Col6a1 is pharmaceutically accessible to a widely used antidiabetic substance, metformin, and Rar modulator. Finally, PDAC tissues from patients with diabetes show an increased expression of COL6A1. Conclusions: Glycemic variability promotes both local invasion and metastatic colonization of PDAC. A pro-metastatic signal axis Rarb/Runx3/Col6a1 whose activity is controlled by glycemic variability is identified. The therapeutic relevance of this pathway needs to be explored in PDAC patients, especially in those with diabetes.

11 Article None 2018

Heining, Christoph / Horak, Peter / Uhrig, Sebastian / Codo, Paula L / Klink, Barbara / Hutter, Barbara / Fröhlich, Martina / Bonekamp, David / Richter, Daniela / Steiger, Katja / Penzel, Roland / Endris, Volker / Ehrenberg, Karl Roland / Frank, Stephanie / Kleinheinz, Kortine / Toprak, Umut H / Schlesner, Matthias / Mandal, Ranadip / Schulz, Lothar / Lambertz, Helmut / Fetscher, Sebastian / Bitzer, Michael / Malek, Nisar P / Horger, Marius / Giese, Nathalia A / Strobel, Oliver / Hackert, Thilo / Springfeld, Christoph / Feuerbach, Lars / Bergmann, Frank / Schröck, Evelin / von Kalle, Christof / Weichert, Wilko / Scholl, Claudia / Ball, Claudia R / Stenzinger, Albrecht / Brors, Benedikt / Fröhling, Stefan / Glimm, Hanno. ·Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany. · University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. · German Cancer Research Center (DKFZ), Heidelberg, Germany. · German Cancer Consortium (DKTK), Dresden, Germany. · Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, Heidelberg, Germany. · Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany. · DKTK, Heidelberg, Germany. · Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany. · Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. · Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany. · Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. · National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany. · Division of Radiology, DKFZ, Heidelberg, Germany. · Institute of Pathology, Technical University Munich, Munich, Germany. · DKTK, Munich, Germany. · Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. · Department of Medical Oncology, NCT, Heidelberg, Germany. · Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany. · Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, Heidelberg, Germany. · Bioinformatics and Omics Data Analytics, DKFZ, Heidelberg, Germany. · Division of Applied Functional Genomics, DKFZ, Heidelberg, Germany. · Department of Oncology, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany. · Department of Oncology, Sana Kliniken Lübeck, Lübeck, Germany. · Department of Gastroenterology, Hepatology and Infectious Diseases, Tübingen University Hospital, Tübingen, Germany. · DKTK, Tübingen, Germany. · Department of Radiology, Tübingen University Hospital, Tübingen, Germany. · Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany. · DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany. · Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, Heidelberg, Germany. hanno.glimm@nct-dresden.de stefan.froehling@nct-heidelberg.de. · Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany. hanno.glimm@nct-dresden.de stefan.froehling@nct-heidelberg.de. ·Cancer Discov · Pubmed #29802158.

ABSTRACT: We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with

12 Article Stromal heterogeneity in pancreatic cancer and chronic pancreatitis. 2018

Haeberle, Lena / Steiger, Katja / Schlitter, Anna Melissa / Safi, Sami Alexander / Knoefel, Wolfram Trudo / Erkan, Mert / Esposito, Irene. ·Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Duesseldorf, Germany. · Institute of Pathology, Technische Universitaet Muenchen, Munich, Germany. · Department of Surgery, University Hospital of Duesseldorf, Duesseldorf, Germany. · Department of Surgery, Koc University Hospital, Istanbul, Turkey. · Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Duesseldorf, Germany. Electronic address: irene.esposito@med.uni-duesseldorf.de. ·Pancreatology · Pubmed #29778400.

ABSTRACT: BACKGROUND/OBJECTIVES: An abundant stromal reaction is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). The cells mainly responsible for the stromal reaction are activated pancreatic stellate cells (PSCs). Despite their crucial role, PSCs are not well characterized. PSCs share characteristics with the better-known hepatic stellate cells (HSCs). The aim of this study was a detailed analysis of PSCs in PDAC and CP. METHODS: Whole-slide specimens of CP (n = 12) and PDAC (n = 10) were studied by histochemistry and immunohistochemistry. The stroma was evaluated using Movat's pentachrome stain. PSCs were tested by immunohistochemistry for PSC markers (α-SMA, CD34, desmin, NGFR, SPARC and tenascin C) and HSC markers (α-crystallin B, CD56, NGF, NT-3, synaptophysin and TrkC). Alpha-SMA, tenascin C, SPARC and NT-3 staining were verified on tissue micro arrays (TMAs) from a well-characterized cohort of 223 PDAC patients. PSCs isolated from human PDAC and CP tissue samples as well as HSCs were evaluated by immunofluorescence. RESULTS: While the stroma of CP cases was characterized by a collagen-rich fibrosis, PDAC stroma displayed higher mucin content (p = 0.0002). PSCs showed variable expression of tested markers. In PDAC samples, staining of most markers was found around tumor complexes, while CP samples showed a greater variety of localizations. Alpha-SMA staining correlated with collagen-rich fibrosis (p = 0.012), while NT-3 staining correlated with mucin-rich stroma (p = 0.008). A peritumoral staining was confirmed for α-SMA, tenascin C, SPARC and NT-3 in the PDAC TMA cohort (n = 223). In a subgroup of patients with pancreatic head tumors and UICC 2009 IIB (n = 144), α-SMA staining intensity was a prognostic factor for overall survival at uni- and multivariate analysis (p = 0.036 and p = 0.002). CONCLUSIONS: The close similarities between PSCs and HSCs were confirmed. Heterogeneous expression patterns of the tested markers might reflect different levels of activation or differentiation, or even multiple subpopulations of PSCs. Survival analysis suggests an impact of stromal composition on survival.

13 Article Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3. 2018

Konukiewitz, Björn / Jesinghaus, Moritz / Steiger, Katja / Schlitter, Anna Melissa / Kasajima, Atsuko / Sipos, Bence / Zamboni, Giuseppe / Weichert, Wilko / Pfarr, Nicole / Klöppel, Günter. ·Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: b.konukiewitz@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: moritz.jesinghaus@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: katja.steiger@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: melissa.schlitter@web.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: atsuko.kasajima@tum.de. · Institute of Pathology, University Hospital of Tuebingen, 72076 Tuebingen, Germany. Electronic address: Bence.Sipos@med.uni-tuebingen.de. · Institute of Pathology, Sacro Cuore Don Calabria Hospital, 37024 Negrar, Verona, Italy. Electronic address: giuseppe.zamboni@sacrocuore.it. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: wilko.weichert@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: nicole.pfarr@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: guenter.kloeppel@alumni.uni-kiel.de. ·Hum Pathol · Pubmed #29596894.

ABSTRACT: Pancreatic neuroendocrine carcinoma is a rare aggressive tumor commonly harboring TP53 and RB1 alterations and lacking neuroendocrine-related genetic changes such as mutations in MEN1 and ATRX/DAXX. Little is known about its genetic profile with regard to that of pancreatic ductal adenocarcinoma. We therefore conducted a detailed genetic study in 12 pancreatic neuroendocrine carcinomas of large cell (n = 9) and small cell type (n = 3) using massive parallel sequencing applying a 409-gene panel on an Ion Torrent system. The genetic data were compared with known data of pancreatic ductal adenocarcinoma and correlated with exocrine lineage marker expression. A similar analysis was performed in 11 pancreatic neuroendocrine tumors G3. Neuroendocrine carcinomas harbored 63 somatic mutations in 45 different genes, affecting most commonly TP53 (8/12 cases), KRAS (5/12 cases), and RB1 (loss of expression with or without deletion in 4/12 cases). Five carcinomas had both TP53 and KRAS mutations. Neuroendocrine tumors G3 only shared singular mutations in 5 different genes with neuroendocrine carcinomas, including TP53, CDKN2A, ARID1A, LRP1B, and APC, affecting 5 different cases. Most KRAS-positive neuroendocrine carcinomas also expressed MUC1 (4/5) and carcinoembryonic antigen (3/5) as markers of ductal differentiation. Our data indicate that almost half of the pancreatic neuroendocrine carcinomas are genetically and phenotypically related to pancreatic ductal adenocarcinoma, and might therefore respond to chemotherapies targeting the latter carcinomas.

14 Article Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. 2018

Mueller, Sebastian / Engleitner, Thomas / Maresch, Roman / Zukowska, Magdalena / Lange, Sebastian / Kaltenbacher, Thorsten / Konukiewitz, Björn / Öllinger, Rupert / Zwiebel, Maximilian / Strong, Alex / Yen, Hsi-Yu / Banerjee, Ruby / Louzada, Sandra / Fu, Beiyuan / Seidler, Barbara / Götzfried, Juliana / Schuck, Kathleen / Hassan, Zonera / Arbeiter, Andreas / Schönhuber, Nina / Klein, Sabine / Veltkamp, Christian / Friedrich, Mathias / Rad, Lena / Barenboim, Maxim / Ziegenhain, Christoph / Hess, Julia / Dovey, Oliver M / Eser, Stefan / Parekh, Swati / Constantino-Casas, Fernando / de la Rosa, Jorge / Sierra, Marta I / Fraga, Mario / Mayerle, Julia / Klöppel, Günter / Cadiñanos, Juan / Liu, Pentao / Vassiliou, George / Weichert, Wilko / Steiger, Katja / Enard, Wolfgang / Schmid, Roland M / Yang, Fengtang / Unger, Kristian / Schneider, Günter / Varela, Ignacio / Bradley, Allan / Saur, Dieter / Rad, Roland. ·Center for Translational Cancer Research (TranslaTUM), Technische Universität München, 81675 Munich, Germany. · Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. · Institute of Pathology, Technische Universität München, 81675 Munich, Germany. · The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK. · Comparative Experimental Pathology, Technische Universität München, 81675 Munich, Germany. · Anthropology & Human Genomics, Department of Biology II, Ludwig-Maximilians Universität, 82152 Martinsried, Germany. · Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, 85764 Neuherberg, Germany. · Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK. · Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), 33193 Oviedo, Spain. · Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain. · Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33011 Oviedo, Spain. · Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo, 33940 El Entrego, Spain. · Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern, 81377 Munich, Germany. · Instituto de Biomedicina y Biotecnología de Cantabria (UC-CSIC), 39012 Santander, Spain. ·Nature · Pubmed #29364867.

ABSTRACT: The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest Kras

15 Article Pancreatic Ductal Adenocarcinoma Subtyping Using the Biomarkers Hepatocyte Nuclear Factor-1A and Cytokeratin-81 Correlates with Outcome and Treatment Response. 2018

Muckenhuber, Alexander / Berger, Anne Katrin / Schlitter, Anna Melissa / Steiger, Katja / Konukiewitz, Björn / Trumpp, Andreas / Eils, Roland / Werner, Jens / Friess, Helmut / Esposito, Irene / Klöppel, Günter / Ceyhan, Güralp O / Jesinghaus, Moritz / Denkert, Carsten / Bahra, Marcus / Stenzinger, Albrecht / Sprick, Martin R / Jäger, Dirk / Springfeld, Christoph / Weichert, Wilko. ·Institute of Pathology, Technical University Munich and German Cancer Consortium (DKTK; partner site Munich), Munich, Germany. · Department of Medical Oncology, Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, Germany. · Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany. · Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH, Heidelberg, Germany. · German Cancer Consortium (DKTK), Heidelberg, Germany. · Division of Theoretical Bioinformatics and Heidelberg Center for Personalised Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany. · Department of Surgery, University Hospital of the Ludwig-Maximilian University, Munich, Germany. · Department of Surgery, University Hospital of the Technical University Munich, Munich, Germany. · Institute of Pathology, University Hospital Düsseldorf, Düsseldorf, Germany. · Institute of Pathology, Charité University Medicine Berlin and German Cancer Consortium (DKTK; partner site Berlin), Berlin, Germany. · Department of Surgery, Charité University Medicine Berlin, Berlin, Germany. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Pathology, Technical University Munich and German Cancer Consortium (DKTK; partner site Munich), Munich, Germany. wilko.weichert@tum.de. ·Clin Cancer Res · Pubmed #29101303.

ABSTRACT:

16 Article Apparent Diffusion Coefficient (ADC) predicts therapy response in pancreatic ductal adenocarcinoma. 2017

Trajkovic-Arsic, M / Heid, I / Steiger, K / Gupta, A / Fingerle, A / Wörner, C / Teichmann, N / Sengkwawoh-Lueong, S / Wenzel, P / Beer, A J / Esposito, I / Braren, R / Siveke, J T. ·Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Institute of Radiology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. · Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany. · 2. Medizinische Klinik, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. · Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. · Department of Nuclear Medicine, University Hospital of Ulm, Ulm, Germany. · Institute of Pathology, University Clinic Duesseldorf, Heinrich-Heine University, Duesseldorf, Germany. · Institute of Radiology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. rbraren@tum.de. · Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. j.siveke@dkfz.de. · German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center (DKFZ), Heidelberg, Germany. j.siveke@dkfz.de. · 2. Medizinische Klinik, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. j.siveke@dkfz.de. ·Sci Rep · Pubmed #29213099.

ABSTRACT: Recent advances in molecular subtyping of Pancreatic Ductal Adenocarcinoma (PDAC) support individualization of therapeutic strategies in this most aggressive disease. With the emergence of various novel therapeutic strategies and neoadjuvant approaches in this quickly deteriorating disease, robust approaches for fast evaluation of therapy response are urgently needed. To this aim, we designed a preclinical imaging-guided therapy trial where genetically engineered mice harboring endogenous aggressive PDAC were treated with the MEK targeting drug refametinib, which induces rapid and profound tumor regression in this model system. Multi-parametric non-invasive imaging was used for therapy response monitoring. A significant increase in the Diffusion-Weighted Magnetic Resonance Imaging derived Apparent Diffusion Coefficient (ADC) was noted already 24 hours after treatment onset. Histopathological analyses showed increased apoptosis and matrix remodeling at this time point. Our findings suggest the ADC parameter as an early predictor of therapy response in PDAC.

17 Article Perspective of αvβ6-Integrin Imaging for Clinical Management of Pancreatic Carcinoma and Its Precursor Lesions. 2017

Steiger, Katja / Schlitter, Anna-Melissa / Weichert, Wilko / Esposito, Irene / Wester, Hans-Jürgen / Notni, Johannes. ·1 Institute of Pathology, Technische Universität München, Munich, Germany. · 2 German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. · 3 Institute of Pathology, Universitätsklinikum Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany. · 4 Chair of Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany. ·Mol Imaging · Pubmed #28627323.

ABSTRACT: ß

18 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.

19 Article Somatostatin receptor expression related to TP53 and RB1 alterations in pancreatic and extrapancreatic neuroendocrine neoplasms with a Ki67-index above 20. 2017

Konukiewitz, Björn / Schlitter, Anna Melissa / Jesinghaus, Moritz / Pfister, Dominik / Steiger, Katja / Segler, Angela / Agaimy, Abbas / Sipos, Bence / Zamboni, Giuseppe / Weichert, Wilko / Esposito, Irene / Pfarr, Nicole / Klöppel, Günter. ·Institute of Pathology, Technical University of Munich, Munich, Germany. · Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital, Erlangen, Germany. · Institute of Pathology, University Hospital of Tuebingen, Tuebingen, Germany. · Institute of Pathology, Sacro Cuore Hospital of Negrar, Verona, Italy. · Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany. ·Mod Pathol · Pubmed #28059098.

ABSTRACT: Somatostatin receptor 2A expression is a feature of well-differentiated neuroendocrine neoplasms and is important for their diagnosis and therapy. Little is known about somatostatin receptor 2A expression in poorly differentiated neuroendocrine neoplasms in relation to TP53 and RB1 status and how these features may contribute to the separation of well from poorly differentiated neuroendocrine neoplasms with a proliferation index above 20%. This study investigates the expression of somatostatin receptors, p53 and Rb1, and TP53 alterations in pancreatic and extrapancreatic well and poorly differentiated neuroendocrine neoplasms (Ki67-index >20%). Thirty-seven poorly differentiated neuroendocrine neoplasms of pancreatic (n=12) and extrapancreatic origin (n=25) as well as 10 well-differentiated neuroendocrine neoplasms of the pancreas (n=9) and rectum (n=1) with a Ki67-index >20% were immunostained for synaptophysin, chromogranin A, Ki67, CD56, p53, Rb1, ATRX, DAXX, progesterone receptor, somatostatin receptor 2A, somatostatin receptor 5, and cytokeratin 20, and sequenced for TP53, exons 5-9. Somatostatin receptor 2A was positive in 6/37 of poorly differentiated and in 8/10 of well-differentiated neuroendocrine neoplasms. One well-differentiated and two poorly differentiated neuroendocrine neoplasms expressed somatostatin receptor 5. Abnormal nuclear p53 and Rb1 staining was found in 29/37 and 22/37 poorly differentiated neuroendocrine neoplasms, respectively, whereas all well-differentiated neuroendocrine neoplasms showed normal p53 and Rb1 expression. TP53 gene alterations were restricted to poorly differentiated neuroendocrine neoplasms (24/34) and correlated well with p53 expression. All cases were progesterone receptor negative. Somatostatin receptor 2A expression is not limited to well-differentiated neuroendocrine neoplasms but also occurs in 16% of poorly differentiated neuroendocrine neoplasms from various sites. Most poorly differentiated neuroendocrine neoplasms are characterized by TP53 alterations and Rb1 loss, usually in the absence of somatostatin receptor 2A expression. In the pancreas, these criteria contribute to separate well-differentiated neuroendocrine neoplasms with a Ki67-index above 20% from poorly differentiated neuroendocrine neoplasms.

20 Article ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation. 2017

Dumartin, L / Alrawashdeh, W / Trabulo, S M / Radon, T P / Steiger, K / Feakins, R M / di Magliano, M P / Heeschen, C / Esposito, I / Lemoine, N R / Crnogorac-Jurcevic, T. ·Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. · Centre for Stem Cells in Cancer &Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK. · Institute of Pathology, Technische Universität München, Munich, Germany. · Department of Histopathology, Royal London Hospital, London, UK. · Department of Surgery, Cell and Developmental Biology, University of Michigan, Ann Arbor, USA. · Institute of Pathology, Heinrich-Heine-University of Düsseldorf, Germany. ·Oncogene · Pubmed #27941872.

ABSTRACT: The mechanisms of initiation of pancreatic ductal adenocarcinoma (PDAC) are still largely unknown. In the present study, we analysed the role of anterior gradient-2 (AGR2) in the earliest stages of pancreatic neoplasia. Immunohistochemical analysis of chronic pancreatitis (CP) and peritumoral areas in PDAC tissues showed that AGR2 was present in tubular complexes (TC) and early pancreatic intraepithelial neoplasia (PanINs). Moreover, AGR2 was also found in discrete subpopulations of non-transformed cells neighbouring these pre-neoplastic lesions. In primary cells derived from human patient-derived xenograft (PDX) model, flow-cytometry revealed that AGR2 was overexpressed in pancreatic cancer stem cells (CSC) compared with non-stem cancer cells. In LSL-Kras

21 Article Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer. 2017

Heid, Irina / Steiger, Katja / Trajkovic-Arsic, Marija / Settles, Marcus / Eßwein, Manuela R / Erkan, Mert / Kleeff, Jörg / Jäger, Carsten / Friess, Helmut / Haller, Bernhard / Steingötter, Andreas / Schmid, Roland M / Schwaiger, Markus / Rummeny, Ernst J / Esposito, Irene / Siveke, Jens T / Braren, Rickmer F. ·Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Germany. · Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Germany. · 2nd Medical Department, Klinikum rechts der Isar, Technische Universität München, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), partner site Essen, University Hospital Essen, Essen, Germany. · Department of Surgery, Koc University School of Medicine, Istanbul, Turkey. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Germany. · Institute of Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technische Universität München, Germany. · Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland. · Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Germany. · Institute of Pathology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany. rbraren@tum.de j.siveke@dkfz-heidelberg.de Irene.Esposito@med.uni-duesseldorf.de. · 2nd Medical Department, Klinikum rechts der Isar, Technische Universität München, Germany. rbraren@tum.de j.siveke@dkfz-heidelberg.de Irene.Esposito@med.uni-duesseldorf.de. · Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Germany. rbraren@tum.de j.siveke@dkfz-heidelberg.de Irene.Esposito@med.uni-duesseldorf.de. ·Clin Cancer Res · Pubmed #27663591.

ABSTRACT:

22 Article Hes1 Controls Exocrine Cell Plasticity and Restricts Development of Pancreatic Ductal Adenocarcinoma in a Mouse Model. 2016

Hidalgo-Sastre, Ana / Brodylo, Roxanne L / Lubeseder-Martellato, Clara / Sipos, Bence / Steiger, Katja / Lee, Marcel / von Figura, Guido / Grünwald, Barbara / Zhong, Suyang / Trajkovic-Arsic, Marija / Neff, Florian / Schmid, Roland M / Siveke, Jens T. ·II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Department of Pathology, University Hospital Tübingen, Tübingen, Germany. · Comparative Experimental Pathology Unit, Institute for General Pathology and Pathological Anatomy, Technical University of Munich, Munich, Germany. · Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany. · German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany. · II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. Electronic address: j.siveke@dkfz.de. ·Am J Pathol · Pubmed #27639167.

ABSTRACT: Perturbation of pancreatic acinar cell state can lead to acinar-to-ductal metaplasia (ADM), 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

23 Article Administration of Gemcitabine After Pancreatic Tumor Resection in Mice Induces an Antitumor Immune Response Mediated by Natural Killer Cells. 2016

Gürlevik, Engin / Fleischmann-Mundt, Bettina / Brooks, Jennifer / Demir, Ihsan Ekin / Steiger, Katja / Ribback, Silvia / Yevsa, Tetyana / Woller, Norman / Kloos, Arnold / Ostroumov, Dmitrij / Armbrecht, Nina / Manns, Michael P / Dombrowski, Frank / Saborowski, Michael / Kleine, Moritz / Wirth, Thomas C / Oettle, Helmut / Ceyhan, Güralp O / Esposito, Irene / Calvisi, Diego F / Kubicka, Stefan / Kühnel, Florian. ·Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address: guerlevik.engin@gmx.net. · Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Institute of Pathology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany. · Department of Surgery, Hannover Medical School, Hannover, Germany. · Charité University Medicine Berlin, Berlin, Germany. · Institute of Pathology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; Institute of Pathology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. · Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany; Cancer Center Reutlingen, District Hospital, Reutlingen, Germany. · Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address: kuehnel.florian@mh-hannover.de. ·Gastroenterology · Pubmed #27210037.

ABSTRACT: BACKGROUND & AIMS: Even after potentially curative R0 resection, patients with pancreatic ductal adenocarcinoma (PDAC) have a poor prognosis owing to high rates of local recurrence and metastasis to distant organs. However, we have no suitable transgenic animal models for surgical interventions. METHODS: To induce formation of pancreatic tumor foci, we electroporated oncogenic plasmids into pancreata of LSL-KrasG12D × p53fl/fl mice; mutant Kras was expressed in p53fl/fl mice using a sleeping beauty transposon. We co-delivered a transposon encoding a constitutively active form of Akt2 (myrAkt2). Carcinogenesis and histopathologic features of tumors were examined. Metastasis was monitored by bioluminescence imaging. Tumors were resected and mice were given gemcitabine, and tumor recurrence patterns and survival were determined. Immune cells were collected from resection sites and analyzed by flow cytometry and in depletion experiments. RESULTS: After electroporation of oncogenic plasmids, mice developed a single pancreatic tumor nodule with histopathologic features of human PDAC. Pancreatic tumors that expressed myrAkt2 infiltrated the surrounding pancreatic tissue and neurons and became widely metastatic, reflecting the aggressive clinical features of PDAC in patients. Despite early tumor resection, mice died from locally recurring and distant tumors, but adjuvant administration of gemcitabine after tumor resection prolonged survival. In mice given adjuvant gemcitabine or vehicle, gemcitabine significantly inhibited local recurrence of tumors, but not metastasis to distant organs, similar to observations in clinical trials. Gemcitabine inhibited accumulation of CD11b+Gr1intF4/80int myeloid-derived suppressor cells at the resection margin and increased the number of natural killer (NK) cells at this location. NK cells but not T cells were required for gemcitabine-mediated antitumor responses. CONCLUSIONS: Gemcitabine administration after resection of pancreatic tumors in mice activates NK cell-mediated antitumor responses and inhibits local recurrence of tumors, consistent with observations from patients with PDAC. Transgenic mice with resectable pancreatic tumors might be promising tools to study adjuvant therapy strategies for patients.

24 Article Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice. 2016

Maresch, Roman / Mueller, Sebastian / Veltkamp, Christian / Öllinger, Rupert / Friedrich, Mathias / Heid, Irina / Steiger, Katja / Weber, Julia / Engleitner, Thomas / Barenboim, Maxim / Klein, Sabine / Louzada, Sandra / Banerjee, Ruby / Strong, Alexander / Stauber, Teresa / Gross, Nina / Geumann, Ulf / Lange, Sebastian / Ringelhan, Marc / Varela, Ignacio / Unger, Kristian / Yang, Fengtang / Schmid, Roland M / Vassiliou, George S / Braren, Rickmer / Schneider, Günter / Heikenwalder, Mathias / Bradley, Allan / Saur, Dieter / Rad, Roland. ·Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. · Institute of Radiology, Klinikum rechts der Isar, Technischen Universität München, 81675 Munich, Germany. · Department of Pathology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · Institute of Virology, Technische Universität München/Helmholtz Zentrum München, 81675 Munich, Germany. · Instituto de Biomedicina y Biotecnología de Cantabria, 39011 Santander, Spain. · Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, 85764 Neuherberg, Germany. · Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ·Nat Commun · Pubmed #26916719.

ABSTRACT: Mouse transgenesis has provided fundamental insights into pancreatic cancer, but is limited by the long duration of allele/model generation. Here we show transfection-based multiplexed delivery of CRISPR/Cas9 to the pancreas of adult mice, allowing simultaneous editing of multiple gene sets in individual cells. We use the method to induce pancreatic cancer and exploit CRISPR/Cas9 mutational signatures for phylogenetic tracking of metastatic disease. Our results demonstrate that CRISPR/Cas9-multiplexing enables key applications, such as combinatorial gene-network analysis, in vivo synthetic lethality screening and chromosome engineering. Negative-selection screening in the pancreas using multiplexed-CRISPR/Cas9 confirms the vulnerability of pancreatic cells to Brca2-inactivation in a Kras-mutant context. We also demonstrate modelling of chromosomal deletions and targeted somatic engineering of inter-chromosomal translocations, offering multifaceted opportunities to study complex structural variation, a hallmark of pancreatic cancer. The low-frequency mosaic pattern of transfection-based CRISPR/Cas9 delivery faithfully recapitulates the stochastic nature of human tumorigenesis, supporting wide applicability for biological/preclinical research.

25 Article Modeling Therapy Response and Spatial Tissue Distribution of Erlotinib in Pancreatic Cancer. 2016

Grüner, Barbara M / Winkelmann, Isabel / Feuchtinger, Annette / Sun, Na / Balluff, Benjamin / Teichmann, Nicole / Herner, Alexander / Kalideris, Evdokia / Steiger, Katja / Braren, Rickmer / Aichler, Michaela / Esposito, Irene / Schmid, Roland M / Walch, Axel / Siveke, Jens T. ·2. Medizinische Klinik, Technische Universität München, Munich, Germany. · Research Unit Analytical Pathology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany. · Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. · Institute of Pathology, Technische Universität München, Munich, Germany. · Institute of Radiology, Technische Universität München, Munich, Germany. · Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany. · 2. Medizinische Klinik, Technische Universität München, Munich, Germany. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Research Unit Analytical Pathology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany. j.siveke@dkfz.de axel.walch@helmholtz-muenchen.de. · 2. Medizinische Klinik, Technische Universität München, Munich, Germany. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK) Partner Site Essen, West German Cancer Center, University Hospital Essen, Essen, Germany. j.siveke@dkfz.de axel.walch@helmholtz-muenchen.de. ·Mol Cancer Ther · Pubmed #26823494.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is likely the most aggressive and therapy-resistant of all cancers. The aim of this study was to investigate the emerging technology of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) as a powerful tool to study drug delivery and spatial tissue distribution in PDAC. We utilized an established genetically engineered mouse model of spontaneous PDAC to examine the distribution of the small-molecule inhibitor erlotinib in healthy pancreas and PDAC. MALDI IMS was utilized on sections of single-dose or long-term-treated mice to measure drug tissue distribution. Histologic and statistical analyses were performed to correlate morphology, drug distribution, and survival. We found that erlotinib levels were significantly lower in PDAC compared with healthy tissue (P = 0.0078). Survival of long-term-treated mice did not correlate with overall levels of erlotinib or with overall histologic tumor grade but did correlate both with the percentage of atypical glands in the cancer (P = 0.021, rs = 0.59) and the level of erlotinib in those atypical glands (P = 0.019, rs = 0.60). The results of this pilot study present MALDI IMS as a reliable technology to study drug delivery and spatial distribution of compounds in a preclinical setting and support drug imaging-based translational approaches. Mol Cancer Ther; 15(5); 1145-52. ©2016 AACR.

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