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Pancreatic Neoplasms: HELP
Articles by Maximilian Reichert
Based on 21 articles published since 2010
(Why 21 articles?)
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Between 2010 and 2020, Maximilian Reichert wrote the following 21 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Oncogenic KRAS and the EGFR loop in pancreatic carcinogenesis-A connection to licensing nodes. 2018

Schneeweis, Christian / Wirth, Matthias / Saur, Dieter / Reichert, Maximilian / Schneider, Günter. ·a II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München , München , Germany. · b German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) , Heidelberg , Germany. ·Small GTPases · Pubmed #27880072.

ABSTRACT: EGFR signaling has a critical role in oncogenic KRAS-driven tumorigenesis of the pancreas, whereas it is dispensable in other organs. The complex signaling network engaged by oncogenic KRAS and its modulation by EGFR signaling, remains incompletely understood. In order to study early signaling events activated by oncogenic KRAS in the pancreas, we recently developed a novel model system based on murine primary pancreatic epithelial cells enabling the time-specific expression of mutant Kras

2 Review Pancreatic ductal cells in development, regeneration, and neoplasia. 2011

Reichert, Maximilian / Rustgi, Anil K. ·Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. ·J Clin Invest · Pubmed #22133881.

ABSTRACT: The pancreas is a complex organ comprised of three critical cell lineages: islet (endocrine), acinar, and ductal. This review will focus upon recent insights and advances in the biology of pancreatic ductal cells. In particular, emphasis will be placed upon the regulation of ductal cells by specific transcriptional factors during development as well as the underpinnings of acinar-ductal metaplasia as an important adaptive response during injury and regeneration. We also address the potential contributions of ductal cells to neoplastic transformation, specifically in pancreatic ductal adenocarcinoma.

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 PRRX1 isoforms cooperate with FOXM1 to regulate the DNA damage response in pancreatic cancer cells. 2019

Marchand, Benoît / Pitarresi, Jason R / Reichert, Maximilian / Suzuki, Kensuke / Laczkó, Dorottya / Rustgi, Anil K. ·Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. · Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. · II. Medizinische Klinik, Technical University of Munich, 81675, Munich, Germany. · Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. · Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. anil2@pennmedicine.upenn.edu. · Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. anil2@pennmedicine.upenn.edu. · Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. anil2@pennmedicine.upenn.edu. ·Oncogene · Pubmed #30705403.

ABSTRACT: PRRX1 is a homeodomain transcriptional factor, which has two isoforms, PRXX1A and PRRX1B. The PRRX1 isoforms have been demonstrated to be important in pancreatic cancer, especially in the regulation of epithelial-to-mesenchymal transition (EMT) in Pancreatic Ductal Adenocarcinoma (PDAC) and of mesenchymal-to-epithelial transition (MET) in liver metastasis. In order to determine the functional underpinnings of PRRX1 and its isoforms, we have unraveled a new interplay between PRRX1 and the FOXM1 transcriptional factors. Our detailed biochemical analysis reveals the direct physical interaction between PRRX1 and FOXM1 proteins that requires the PRRX1A/B 200-222/217 amino acid (aa) region and the FOXM1 Forkhead domain. Additionally, we demonstrate the cooperation between PRRX1 and FOXM1 in the regulation of FOXM1-dependent transcriptional activity. Moreover, we establish FOXM1 as a critical downstream target of PRRX1 in pancreatic cancer cells. We demonstrate a novel role for PRRX1 in the regulation of genes involved in DNA repair pathways. Indeed, we show that expression of PRRX1 isoforms may limit the induction of DNA damage in pancreatic cancer cells. Finally, we demonstrate that targeting FOXM1 with the small molecule inhibitor FDI6 suppress pancreatic cancer cell proliferation and induces their apoptotic cell death. FDI6 sensitizes pancreatic cancer cells to Etoposide and Gemcitabine induced apoptosis. Our data provide new insights into PRRX1's involvement in regulating DNA damage and provide evidence of a possible PRRX1-FOXM1 axis that is critical for PDAC cells.

5 Article Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness. 2018

Renz, Bernhard W / Tanaka, Takayuki / Sunagawa, Masaki / Takahashi, Ryota / Jiang, Zhengyu / Macchini, Marina / Dantes, Zahra / Valenti, Giovanni / White, Ruth A / Middelhoff, Moritz A / Ilmer, Matthias / Oberstein, Paul E / Angele, Martin K / Deng, Huan / Hayakawa, Yoku / Westphalen, C Benedikt / Werner, Jens / Remotti, Helen / Reichert, Maximilian / Tailor, Yagnesh H / Nagar, Karan / Friedman, Richard A / Iuga, Alina C / Olive, Kenneth P / Wang, Timothy C. ·Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto, Nagasaki, Japan. · Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Division of Oncology, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. · Department of Pathology, and Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. · Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. · Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York. · Biomedical Informatics Shared Resource of the Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics, Columbia University Medical Center, New York, New York. · Department of Pathology and Cell Biology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. tcw21@columbia.edu. ·Cancer Discov · Pubmed #30185628.

ABSTRACT: In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL-

6 Article Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer. 2018

Reichert, Maximilian / Bakir, Basil / Moreira, Leticia / Pitarresi, Jason R / Feldmann, Karin / Simon, Lauren / Suzuki, Kensuke / Maddipati, Ravikanth / Rhim, Andrew D / Schlitter, Anna M / Kriegsmann, Mark / Weichert, Wilko / Wirth, Matthias / Schuck, Kathleen / Schneider, Günter / Saur, Dieter / Reynolds, Albert B / Klein-Szanto, Andres J / Pehlivanoglu, Burcin / Memis, Bahar / Adsay, N Volkan / Rustgi, Anil K. ·Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University Munich, Medizinische Klinik, Ismaninger Str. 22, Munich 81675, Germany. Electronic address: maximilian.reichert@tum.de. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), IDIBAPS, University of Barcelona, Catalonia, Spain. · Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University Munich, Medizinische Klinik, Ismaninger Str. 22, Munich 81675, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. · Division of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center, Houston, TX, USA. · Institute of General Pathology and Pathological Anatomy, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. · Institute of Pathology, Heidelberg University, Heidelberg, Germany. · Institute of Pathology, Heinrich-Heine University and University Hospital Düsseldorf, Düsseldorf 40225, Germany. · Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA. · Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA, USA. · Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA, USA. · Department of Pathology, Koc University Hospital, Istanbul, Turkey. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA. Electronic address: anil2@pennmedicine.upenn.edu. ·Dev Cell · Pubmed #29920275.

ABSTRACT: The regulation of metastatic organotropism in pancreatic ductal a denocarcinoma (PDAC) remains poorly understood. We demonstrate, using multiple mouse models, that liver and lung metastatic organotropism is dependent upon p120catenin (p120ctn)-mediated epithelial identity. Mono-allelic p120ctn loss accelerates Kras

7 Article Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. 2018

Ruess, Dietrich A / Heynen, Guus J / Ciecielski, Katrin J / Ai, Jiaoyu / Berninger, Alexandra / Kabacaoglu, Derya / Görgülü, Kivanc / Dantes, Zahra / Wörmann, Sonja M / Diakopoulos, Kalliope N / Karpathaki, Angeliki F / Kowalska, Marlena / Kaya-Aksoy, Ezgi / Song, Liang / van der Laan, Eveline A Zeeuw / López-Alberca, María P / Nazaré, Marc / Reichert, Maximilian / Saur, Dieter / Erkan, Mert M / Hopt, Ulrich T / Sainz, Bruno / Birchmeier, Walter / Schmid, Roland M / Lesina, Marina / Algül, Hana. ·Mildred-Scheel-Chair of Tumor Metabolism, Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Surgery, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany. · Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, Berlin, Germany. · Medicinal Chemistry, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany. · Koç University School of Medicine, Istanbul, Turkey. · Department of Biochemistry, Autónoma University of Madrid, School of Medicine, Instituto de Investigaciones Biomédicas "Alberto Sols", Madrid, Spain. · Mildred-Scheel-Chair of Tumor Metabolism, Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. hana.alguel@mri.tum.de. ·Nat Med · Pubmed #29808009.

ABSTRACT: The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors

8 Article MTOR inhibitor-based combination therapies for pancreatic cancer. 2018

Hassan, Zonera / Schneeweis, Christian / Wirth, Matthias / Veltkamp, Christian / Dantes, Zahra / Feuerecker, Benedikt / Ceyhan, Güralp O / Knauer, Shirley K / Weichert, Wilko / Schmid, Roland M / Stauber, Roland / Arlt, Alexander / Krämer, Oliver H / Rad, Roland / Reichert, Maximilian / Saur, Dieter / Schneider, Günter. ·Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany. · Institute of Pathology, Heinrich-Heine University and University Hospital Düsseldorf, 40225 Düsseldorf, Germany. · Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. · Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, 81675 München, Germany. · Molecular Biology, Centre for Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany. · Institute of Pathology, Technische Universität München, 81675 München, Germany. · Molecular and Cellular Oncology/ENT, University Medical Center Mainz, Langenbeckstrasse 1, Mainz 55131, Germany. · Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany. · Department of Toxicology, University of Mainz Medical Center, Mainz 55131, Germany. · Division of Gastroenterology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ·Br J Cancer · Pubmed #29384525.

ABSTRACT: BACKGROUND: Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification. METHODS: We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance. Cross-species validation and pharmacological intervention studies were used to recapitulate genetic data in human models, including primary human 3D PDAC cultures. RESULTS: Genetic deletion of the Mtor gene in the pancreas results in exocrine and endocrine insufficiency. In established murine PDAC cells, MTOR is linked to metabolic pathways and maintains the glucose uptake and growth. Importantly, blocking MTOR genetically as well as pharmacologically results in adaptive rewiring of oncogenic signalling with activation of canonical extracellular signal-regulated kinase and phosphoinositide 3-kinase-AKT pathways. We provide evidence that interfering with such adaptive signalling in murine and human PDAC models is important in a subgroup. CONCLUSIONS: Our data suggest developing dual MTORC1/TORC2 inhibitor-based therapies for subtype-specific intervention.

9 Article β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. 2018

Renz, Bernhard W / Takahashi, Ryota / Tanaka, Takayuki / Macchini, Marina / Hayakawa, Yoku / Dantes, Zahra / Maurer, H Carlo / Chen, Xiaowei / Jiang, Zhengyu / Westphalen, C Benedikt / Ilmer, Matthias / Valenti, Giovanni / Mohanta, Sarajo K / Habenicht, Andreas J R / Middelhoff, Moritz / Chu, Timothy / Nagar, Karan / Tailor, Yagnesh / Casadei, Riccardo / Di Marco, Mariacristina / Kleespies, Axel / Friedman, Richard A / Remotti, Helen / Reichert, Maximilian / Worthley, Daniel L / Neumann, Jens / Werner, Jens / Iuga, Alina C / Olive, Kenneth P / Wang, Timothy C. ·Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, 81377 Munich, Germany; Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. · Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Internal Medicine III, Hospital of the University of Munich, 81377 Munich, Germany. · Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, 81377 Munich, Germany. · Institute for Cardiovascular Prevention, University of Munich, 80336 Munich, Germany. · Department of Internal Medicine and Surgery (DIMEC), Alma Mater Studiorum, University of Bologna, Sant'Orsola-Malpighi Hospital, 40138 Bologna, Italy. · Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, 40138 Bologna, Italy. · Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia. · Department of Pathology, Hospital of the University of Munich, 81377 Munich, Germany. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu. ·Cancer Cell · Pubmed #29249692.

ABSTRACT: Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras

10 Article ETS-Transcription Factor ETV1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer. 2016

Heeg, Steffen / Das, Koushik K / Reichert, Maximilian / Bakir, Basil / Takano, Shigetsugu / Caspers, Julia / Aiello, Nicole M / Wu, Katherine / Neesse, Albrecht / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Hicks, Philip / Rustgi, Anil K. ·Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine II, Medical Center, University of Freiburg; Freiburg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; II. Medizinische Klinik, Technical University of Munich, Munich, Germany. · Department of Medicine II, Medical Center, University of Freiburg; Freiburg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Division of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Goettingen, Goettingen, Germany. · University of Texas, MD Anderson Cancer Center, Houston, Texas. · David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: anil2@mail.med.upenn.edu. ·Gastroenterology · Pubmed #27318148.

ABSTRACT: BACKGROUND & AIMS: The ETS-transcription factor ETV1 is involved in epithelial-mesenchymal transition during pancreatic development and is induced in mouse pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). We investigated the function of ETV1 in stromal expansion of PDAC and metastasis, as well as its effects on a novel downstream target Sparc, which encodes a matricellular protein found in PDAC stroma that has been associated with invasiveness, metastasis and poor patient outcomes. METHODS: Pancreatic ductal cells were isolated from Pdx1Cre;Kras(G12D/+) mice (PanIN), Pdx1Cre;Kras(G12D/+);p53(fl/+) and Pdx1Cre;Kras(G12D/+);p53(fl/+);Rosa26(YFP) mice (PDAC), and Pdx1Cre;Kras(G12D/+);p53(fl/+);Sparc(-/-) mice. Cells were grown in 3-dimensional organoid culture to analyze morphology, proliferation, and invasion. Human PanIN and PDAC tissues were evaluated for ETV1 expression. Orthotopic pancreatic transplants of ETV1-overexpressing PDAC and respective control cells were performed. RESULTS: ETV1 expression was significantly increased in human PanINs and, even more so, in primary and metastatic PDAC. Analyses of mouse orthotopic xenografts revealed that ETV1 induced significantly larger primary tumors than controls, with significantly increased stromal expansion, ascites and metastases. In 3-dimensional organoids, ETV1 disrupted cyst architecture, induced EMT, and increased invasive capacity. Furthermore, we identified Sparc as a novel functional gene target of Etv1 by luciferase assays, and SPARC and ETV1 proteins co-localized in vivo. Disruption of Sparc abrogates the phenotype of stromal expansion and metastasis found with ETV1 overexpression in vivo. We identified hyaluronan synthase 2 (Has2) as another novel downstream factor of Etv1; that may mediate ETV1's significant expansion of hyaluronic acid in PDAC stroma. Conversely, disruption of Etv1 in PDAC mice (Pdx1Cre;Kras(G12D/+);p53(fl/+);Rosa26(YFP);Cre;Etv1(fl/fl)) reduced levels of SPARC and hyaluronic acid in the stroma. CONCLUSIONS: ETV1 is critical in the desmoplastic stromal expansion and metastatic progression of pancreatic cancer in mice, mediated functionally in part through Sparc and Has2.

11 Article Membranous CD24 drives the epithelial phenotype of pancreatic cancer. 2016

Lubeseder-Martellato, Clara / Hidalgo-Sastre, Ana / Hartmann, Carolin / Alexandrow, Katharina / Kamyabi-Moghaddam, Zahra / Sipos, Bence / Wirth, Matthias / Neff, Florian / Reichert, Maximilian / Heid, Irina / Schneider, Günter / Braren, Rickmer / Schmid, Roland M / Siveke, Jens T. ·II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Current address: Klinik für Anaesthesiologie, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Institute of Pathology, University Tübingen, Tübingen, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Institute of Radiology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. ·Oncotarget · Pubmed #27203385.

ABSTRACT: Surface CD24 has previously been described, together with CD44 and ESA, for the characterization of putative cancer stem cells in pancreatic ductal adenocarcinoma (PDAC), the most fatal of all solid tumors. CD24 has a variety of biological functions including the regulation of invasiveness and cell proliferation, depending on the tumor entity and subcellular localization. Genetically engineered mouse models (GEMM) expressing oncogenic KrasG12D recapitulate the human disease and develop PDAC. In this study we investigate the function of CD24 using GEMM of endogenous PDAC and a model of cerulein-induced acute pancreatitis. We found that (i) CD24 expression was upregulated in murine and human PDAC and during acute pancreatitis (ii) CD24 was expressed exclusively in differentiated PDAC, whereas CD24 absence was associated with undifferentiated tumors and (iii) membranous CD24 expression determines tumor subpopulations with an epithelial phenotype in grafted models. In addition, we show that CD24 protein is stabilized in response to WNT activation and that overexpression of CD24 in pancreatic cancer cells upregulated β-catenin expression augmenting an epithelial, non-metastatic signature. Our results support a positive feedback model according to which (i) WNT activation and subsequent β-catenin dephosphorylation stabilize CD24 protein expression, and (ii) sustained CD24 expression upregulates β-catenin expression. Eventually, membranous CD24 augments the epithelial phenotype of pancreatic tumors. Thus we link the WNT/β-catenin pathway with the regulation of CD24 in the context of PDAC differentiation.

12 Article Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis. 2016

Westphalen, C Benedikt / Takemoto, Yoshihiro / Tanaka, Takayuki / Macchini, Marina / Jiang, Zhengyu / Renz, Bernhard W / Chen, Xiaowei / Ormanns, Steffen / Nagar, Karan / Tailor, Yagnesh / May, Randal / Cho, Youngjin / Asfaha, Samuel / Worthley, Daniel L / Hayakawa, Yoku / Urbanska, Aleksandra M / Quante, Michael / Reichert, Maximilian / Broyde, Joshua / Subramaniam, Prem S / Remotti, Helen / Su, Gloria H / Rustgi, Anil K / Friedman, Richard A / Honig, Barry / Califano, Andrea / Houchen, Courtney W / Olive, Kenneth P / Wang, Timothy C. ·Department of Internal Medicine III, Hospital of the University of Munich D-81377, Munich, Germany; Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, 40128 Bologna, Italy. · Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich D-81377, Munich, Germany; Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology, Hospital of the University of Munich D-81377, Munich, Germany. · Department of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, OK 73104, USA. · Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Internal Medicine II, Klinikum rechts der Isar II, Technische Universität München, D-81675 Munich, Germany. · Department of Internal Medicine II, Klinikum rechts der Isar II, Technische Universität München, D-81675 Munich, Germany; Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. · Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Otolaryngology / Head & Neck Surgery, Columbia University Medical Center, New York, NY 10032, USA. · Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Otolaryngology / Head & Neck Surgery, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA; Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Center for Computational Biology and Bioinformatics (C2B2), Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu. ·Cell Stem Cell · Pubmed #27058937.

ABSTRACT: The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer.

13 Article Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization. 2016

Takano, Shigetsugu / Reichert, Maximilian / Bakir, Basil / Das, Koushik K / Nishida, Takahiro / Miyazaki, Masaru / Heeg, Steffen / Collins, Meredith A / Marchand, Benoît / Hicks, Philip D / Maitra, Anirban / Rustgi, Anil K. ·Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; II. Medizinische Klinik, Technical University of Munich, Munich 81675, Germany; · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; · Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine II, Medical Center, University of Freiburg, 79106 Freiburg, Germany; · Department of Pathology, Sheikh Ahmad bin Zayed Al Nahyan Pancreatic Cancer Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Translational Molecular Pathology, Sheikh Ahmad bin Zayed Al Nahyan Pancreatic Cancer Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ·Genes Dev · Pubmed #26773005.

ABSTRACT: The two major isoforms of the paired-related homeodomain transcription factor 1 (Prrx1), Prrx1a and Prrx1b, are involved in pancreatic development, pancreatitis, and carcinogenesis, although the biological role that these isoforms serve in the systemic dissemination of pancreatic ductal adenocarcinoma (PDAC) has not been investigated. An epithelial-mesenchymal transition (EMT) is believed to be important for primary tumor progression and dissemination, whereas a mesenchymal-epithelial transition (MET) appears crucial for metastatic colonization. Here, we describe novel roles for both isoforms in the metastatic cascade using complementary in vitro and in vivo models. Prrx1b promotes invasion, tumor dedifferentiation, and EMT. In contrast, Prrx1a stimulates metastatic outgrowth in the liver, tumor differentiation, and MET. We further demonstrate that the switch from Prrx1b to Prrx1a governs EMT plasticity in both mouse models of PDAC and human PDAC. Last, we identify hepatocyte growth factor ( HGF) as a novel transcriptional target of Prrx1b. Targeted therapy of HGF in combination with gemcitabine in a preclinical model of PDAC reduces primary tumor volume and eliminates metastatic disease. Overall, we provide new insights into the isoform-specific roles of Prrx1a and Prrx1b in primary PDAC formation, dissemination, and metastatic colonization, allowing for novel therapeutic strategies targeting EMT plasticity.

14 Article Detection of Tumor Suppressor Genes in Cancer Development by a Novel shRNA-Based Method. 2015

von Burstin, Johannes / Diersch, Sandra / Schneider, Günter / Reichert, Maximilian / Rustgi, Anil K / Schmid, Roland M. ·II. Medizinische Klinik, Technische Universität München, Munich, Germany. johannes.von-burstin@lrz.tum.de. · II. Medizinische Klinik, Technische Universität München, Munich, Germany. · II. Medizinische Klinik, Technische Universität München, Munich, Germany. Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. · Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. ·Mol Cancer Res · Pubmed #25724428.

ABSTRACT: IMPLICATIONS: The combinatory in vitro/in vivo approach described in this study allows for rapid and efficient identification of genes involved in carcinogenesis and opens new avenues for the development of therapeutic strategies to improve cancer treatment.

15 Article An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. 2013

Kim, Jungsun / Hoffman, John P / Alpaugh, R Katherine / Rhim, Andrew D / Reichert, Maximilian / Stanger, Ben Z / Furth, Emma E / Sepulveda, Antonia R / Yuan, Chao-Xing / Won, Kyoung-Jae / Donahue, Greg / Sands, Jessica / Gumbs, Andrew A / Zaret, Kenneth S. ·Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-5157, USA. ·Cell Rep · Pubmed #23791528.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis and lacks a human cell model of early disease progression. When human PDAC cells are injected into immunodeficient mice, they generate advanced-stage cancer. We hypothesized that if human PDAC cells were converted to pluripotency and then allowed to differentiate back into pancreatic tissue, they might undergo early stages of cancer. Although most induced pluripotent stem cell (iPSC) lines were not of the expected cancer genotype, one PDAC line, 10-22 cells, when injected into immunodeficient mice, generated pancreatic intraepithelial neoplasia (PanIN) precursors to PDAC that progressed to the invasive stage. The PanIN-like cells secrete or release proteins from many genes that are known to be expressed in human pancreatic cancer progression and that predicted an HNF4α network in intermediate-stage lesions. Thus, rare events allow iPSC technology to provide a live human cell model of early pancreatic cancer and insights into disease progression.

16 Article ERK2-regulated TIMP1 induces hyperproliferation of K-Ras(G12D)-transformed pancreatic ductal cells. 2013

Botta, Gregory P / Reichert, Maximilian / Reginato, Mauricio J / Heeg, Steffen / Rustgi, Anil K / Lelkes, Peter I. ·Department of Biochemistry and Molecular Biology, Molecular and Cellular Biology and Genetics Program, Drexel University College of Medicine, Philadelphia, PA, USA. ·Neoplasia · Pubmed #23555182.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) commonly contains a mutation in K-Ras(G12D) and is characterized by a desmoplastic reaction composed of deregulated, proliferating cells embedded in an abnormal extracellular matrix (ECM). Our previous observations imply that inhibiting the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK2) kinase signal pathway reverses a matrix metalloproteinase 1-specific invasive phenotype. Here, we investigated the specific genes downstream of MAPK-ERK2 responsible for the hyperproliferative abilities of human and murine primary ductal epithelial cells (PDCs) within an ECM. Compared with control, DNA synthesis and total cell proliferation was significantly increased in human PDCs harboring the PDAC common p53, Rb/p16(INK4a), and K-Ras (G12D) mutations. Both of these effects were readily reversed following small-molecule inhibition or lentiviral silencing of ERK2. Microarray analysis of PDCs in three-dimensional (3D) culture revealed a unique, MAPK-influenced gene signature downstream of K-Ras (G12D). Unbiased hierarchical analysis permitted filtration of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). Pancreatic cells isolated from Pdx1-Cre; LSL-K-ras(G12D/+)-mutated mice exhibit increased TIMP1 RNA transcription compared to wild-type littermate controls. Analyses of both 3D, in vitro human K-Ras (G12D) PDCs and data mining of publicly annotated human pancreatic data sets correlatively indicate increased levels of TIMP1 RNA. While silencing TIMP1 did not significantly effect PDC proliferation, exogenous addition of human recombinant TIMP1 significantly increased proliferation but only in transformed K-Ras (G12D) PDCs in 3D. Overall, TIMP1 is an upregulated gene product and a proliferative inducer of K-Ras(G12D)-mutated PDCs through the ERK2 signaling pathway.

17 Article Efemp1 and p27(Kip1) modulate responsiveness of pancreatic cancer cells towards a dual PI3K/mTOR inhibitor in preclinical models. 2013

Diersch, Sandra / Wenzel, Patrick / Szameitat, Melanie / Eser, Philipp / Paul, Mariel C / Seidler, Barbara / Eser, Stefan / Messer, Marlena / Reichert, Maximilian / Pagel, Philipp / Esposito, Irene / Schmid, Roland M / Saur, Dieter / Schneider, Günter. ·II. Medizinische Klinik, Technische Universität München, München, Germany. ·Oncotarget · Pubmed #23470560.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease with a poor prognosis and targeted therapies have failed in the clinic so far. Several evidences point to the phosphatidylinositol 3-kinase (PI3K)-mTOR pathway as a promising signaling node for targeted therapeutic intervention. Markers, which predict responsiveness of PDAC cells towards PI3K inhibitors are unknown. However, such markers are needed and critical to better stratify patients in clinical trials. We used a large murine Kras(G12D)- and PI3K (p110α(H1047R))-driven PDAC cell line platform to unbiased define modulators of responsiveness towards the dual PI3K-mTOR inhibitor Bez235. In contrast to other tumor models, we show that Kras(G12D)- and PI3K (p110α(H1047R))-driven PDAC cell lines are equally sensitive towards Bez235. In an unbiased approach we found that the extracellular matrix protein Efemp1 controls sensitivity of murine PDAC cells towards Bez235. We show that Efemp1 expression is connected to the cyclin-dependent kinase inhibitor p27(Kip1). In a murine Kras(G12D)-driven PDAC model, p27(Kip1) haploinsufficiency accelerates cancer development in vivo. Furthermore, p27(Kip1) controls Bez235 sensitivity in a gene dose-dependent fashion in murine PDAC cells and lowering of p27(Kip1) decreases Bez235 responsiveness in murine PDAC models. Together, we define the Efemp1-p27(Kip1) axis as a potential marker module of PDAC cell sensitivity towards dual PI3K-mTOR inhibitors, which might help to better stratify patients in clinical trials.

18 Article The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis. 2013

Reichert, Maximilian / Takano, Shigetsugu / von Burstin, Johannes / Kim, Sang-Bae / Lee, Ju-Seog / Ihida-Stansbury, Kaori / Hahn, Christopher / Heeg, Steffen / Schneider, Günter / Rhim, Andrew D / Stanger, Ben Z / Rustgi, Anil K. ·Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, USA. ·Genes Dev · Pubmed #23355395.

ABSTRACT: Pancreatic exocrine cell plasticity can be observed during development, pancreatitis with subsequent regeneration, and also transformation. For example, acinar-ductal metaplasia (ADM) occurs during acute pancreatitis and might be viewed as a prelude to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) development. To elucidate regulatory processes that overlap ductal development, ADM, and the progression of normal cells to PanIN lesions, we undertook a systematic approach to identify the Prrx1 paired homeodomain Prrx1 transcriptional factor as a highly regulated gene in these processes. Prrx1 annotates a subset of pancreatic ductal epithelial cells in Prrx1creER(T2)-IRES-GFP mice. Furthermore, sorted Prrx1(+) cells have the capacity to self-renew and expand during chronic pancreatitis. The two isoforms, Prrx1a and Prrx1b, regulate migration and invasion, respectively, in pancreatic cancer cells. In addition, Prrx1b is enriched in circulating pancreatic cells (Pdx1cre;LSL-Kras(G12D/+);p53(fl/+);R26YFP). Intriguingly, the Prrx1b isoform, which is also induced in ADM, binds the Sox9 promoter and positively regulates Sox9 expression. This suggests a new hierarchical scheme whereby a Prrx1-Sox9 axis may influence the emergence of acinar-ductal metaplasia and regeneration. Furthermore, our data provide a possible explanation of why pancreatic cancer is skewed toward a ductal fate.

19 Article Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death. 2013

Conradt, Laura / Henrich, Annika / Wirth, Matthias / Reichert, Maximilian / Lesina, Marina / Algül, Hana / Schmid, Roland M / Krämer, Oliver H / Saur, Dieter / Schneider, Günter. ·II. Medizinische Klinik, Technische Universität München, München, Germany. ·Int J Cancer · Pubmed #23115126.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) represents the fourth leading cause of cancer death in the western world, with a 5-year survival rate below 5%. Murine double minute 2 (Mdm2) is an important negative regulator of the tumor suppressor p53. Reactivation of wild-type p53 is a promising treatment strategy, and inhibitors of Mdm2 have already entered clinical trials. To investigate the effects of Mdm2 inhibitors in PDAC, we used a murine cell line platform with a genetically defined status of p53. Here, we describe that Mdm2 inhibitors can act on a subset of murine PDAC cell lines p53 independently. Furthermore, we observed that Mdm2 inhibitors increase the sensitivity of murine PDAC cell lines toward topoisomerase II inhibitors by inducing effector caspase-independent cell death. The combination of Mdm2 inhibitors with topoisomerase II inhibitors acts independent of the survival factor NFκB/RelA. Mechanistically, Mdm2 inhibitors increase topoisomerase II inhibitor-induced DNA double-strand breaks. We show that Mdm2 binds to Nbs1 of the Mre11-Rad50-Nijmegen breakage syndrome (Nbs) 1 DNA repair complex. In addition, we provide evidence that Mdm2 inhibitors delay DNA repair. These findings may help to design novel therapeutic strategies to overcome therapeutic resistance of PDAC.

20 Article EMT and dissemination precede pancreatic tumor formation. 2012

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

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

21 Article Constitutive K-RasG12D activation of ERK2 specifically regulates 3D invasion of human pancreatic cancer cells via MMP-1. 2012

Botta, Gregory P / Reginato, Mauricio J / Reichert, Maximilian / Rustgi, Anil K / Lelkes, Peter I. ·Department of Biochemistry and Molecular BiologyDrexel University College of Medicine, Philadelphia, Pennsylvania, USA. ·Mol Cancer Res · Pubmed #22160930.

ABSTRACT: Pancreatic ductal adenocarcinomas (PDAC) are highly invasive and metastatic neoplasms commonly unresponsive to current drug therapy. Overwhelmingly, PDAC harbors early constitutive, oncogenic mutations in K-Ras(G12D) that exist prior to invasion. Histologic and genetic analyses of human PDAC biopsies also exhibit increased expression of extracellular signal-regulated kinase (ERK) 1/2 and proinvasive matrix metalloproteinases (MMP), indicators of poor prognosis. However, the distinct molecular mechanisms necessary for K-Ras/ERK1/2 signaling and its influence on MMP-directed stromal invasion in primary human pancreatic ductal epithelial cells (PDEC) have yet to be elucidated in three-dimensions. Expression of oncogenic K-Ras(G12D) alone in genetically defined PDECs reveals increased invadopodia and epithelial-to-mesenchymal transition markers, but only when cultured in a three-dimensional model incorporating a basement membrane analog. Activation of ERK2, but not ERK1, also occurs only in K-Ras(G12D)-mutated PDECs cultured in three-dimensions and is a necessary intracellular signaling event for invasion based upon pharmacologic and short hairpin RNA (shRNA) inhibition. Increased active invasion of K-Ras(G12D) PDECs through the basement membrane model is associated with a specific microarray gene expression signature and induction of MMP endopeptidases. Specifically, MMP-1 RNA, its secreted protein, and its proteolytic cleavage activity are amplified in K-Ras(G12D) PDECs when assayed by real-time quantitative PCR, ELISA, and fluorescence resonance energy transfer (FRET). Importantly, shRNA silencing of MMP-1 mimics ERK2 inhibition and disrupts active, vertical PDEC invasion. ERK2 isoform and MMP-1 targeting are shown to be viable strategies to attenuate invasion of K-Ras(G12D)-mutated human pancreatic cancer cells in a three-dimensional tumor microenvironment.