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Pancreatic Neoplasms: HELP
Articles by Michael D. Wirth
Based on 15 articles published since 2010
(Why 15 articles?)
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Between 2010 and 2020, M. Wirth wrote the following 15 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 Dietary patterns and risk of pancreatic cancer: a systematic review. 2017

Zheng, Jiali / Guinter, Mark A / Merchant, Anwar T / Wirth, Michael D / Zhang, Jiajia / Stolzenberg-Solomon, Rachael Z / Steck, Susan E. ·Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, USA. · Cancer Prevention and Control Program, University of South Carolina, Columbia, South Carolina, USA. · Connecting Health Innovations LLC, Columbia, South Carolina, USA. · Division of Cancer Epidemiology and Genetics, Nutritional Epidemiology Branch, National Cancer Institute, Rockville, Maryland, USA. ·Nutr Rev · Pubmed #29025004.

ABSTRACT: Context: Pancreatic cancer has the highest case fatality rate of all major cancers. Objective: A systematic review using PRISMA guidelines was conducted to summarize the associations between dietary patterns and risk of pancreatic cancer. Data Sources: PubMed and Web of Science databases were searched for case-control and cohort studies published up to June 15, 2016. Study Selection: Eligible studies included a dietary pattern as exposure and pancreatic cancer incidence or mortality as outcome and reported odds ratios, hazard ratios, or relative risks, along with corresponding 95%CIs. Data Extraction: Important characteristics of each study, along with the dietary assessment instrument, the component foods or nutrients included in each dietary pattern or the scoring algorithm of a priori dietary patterns, were presented. For each dietary pattern identified, the estimate of association and the 95%CI comparing the highest versus the lowest category from the model with the most covariate adjustment were reported. Results: A total of 16 studies were identified. Among the 8 studies that examined data-driven dietary patterns, significant positive associations were found between pancreatic cancer risk and the Animal Products, Starch Rich, and Western dietary patterns, with effect estimates ranging from 1.69 to 2.40. Significant inverse relationships were found between risk of pancreatic cancer and dietary patterns designated as Fruits and Vegetables, Vitamins and Fiber, and Prudent, with effect estimates ranging from 0.51 to 0.55. Eight studies of a priori dietary patterns consistently suggested that improved dietary quality was associated with reduced risk of pancreatic cancer. Conclusions: Better diet quality is associated with reduced risk of pancreatic cancer. The associations between dietary patterns and pancreatic cancer were stronger in case-control studies than in cohort studies and were stronger among men than among women.

3 Review Concepts to Target MYC in Pancreatic Cancer. 2016

Wirth, Matthias / Mahboobi, Siavosh / Krämer, Oliver H / Schneider, Günter. ·II. Medizinische Klinik, Technische Universität München, München, Germany. · Institute of Pharmacy, Department of Pharmaceutical Chemistry I, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany. · Department of Toxicology, University of Mainz Medical Center, Mainz, Germany. · II. Medizinische Klinik, Technische Universität München, München, Germany. guenter.schneider@tum.de. ·Mol Cancer Ther · Pubmed #27406986.

ABSTRACT: Current data suggest that MYC is an important signaling hub and driver in pancreatic ductal adenocarcinoma (PDAC), a tumor entity with a strikingly poor prognosis. No targeted therapies with a meaningful clinical impact were successfully developed against PDAC so far. This points to the need to establish novel concepts targeting the relevant drivers of PDAC, like KRAS or MYC. Here, we discuss recent developments of direct or indirect MYC inhibitors and their potential mode of action in PDAC. Mol Cancer Ther; 15(8); 1792-8. ©2016 AACR.

4 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.

5 Article Diet-related inflammation and risk of prostate cancer in the California Men's Health Study. 2019

McMahon, Daria M / Burch, James B / Hébert, James R / Hardin, James W / Zhang, Jiajia / Wirth, Michael D / Youngstedt, Shawn D / Shivappa, Nitin / Jacobsen, Steven J / Caan, Bette / Van Den Eeden, Stephen K. ·Department of Epidemiology and Biostatistics, University of South Carolina, Columbia. · Department of Epidemiology and Biostatistics, University of South Carolina, Columbia; Cancer Prevention and Control Program, University of South Carolina, Columbia; WJB Dorn Department of Veterans Affairs Medical Center, Columbia, SC. · Department of Epidemiology and Biostatistics, University of South Carolina, Columbia; Cancer Prevention and Control Program, University of South Carolina, Columbia; Connecting Health Innovations, LLC, Columbia, SC. Electronic address: jhebert@sc.edu. · Department of Epidemiology and Biostatistics, University of South Carolina, Columbia; Cancer Prevention and Control Program, University of South Carolina, Columbia; Connecting Health Innovations, LLC, Columbia, SC. · College of Nursing and Health Innovation, Arizona State University, Phoenix; Phoenix VA Health Care System, Phoenix, AZ. · Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena. · Division of Research, Kaiser Permanente Northern California, Oakland. ·Ann Epidemiol · Pubmed #30503073.

ABSTRACT: PURPOSE: The purpose of the study was to examine the relationship between proinflammatory diet and prostate cancer risk. METHODS: Energy-adjusted Dietary Inflammatory Index (E-DII) scores were computed among 40,161 participants in the California Men's Health Study. Over 9.7 ± 3.8 years of follow-up, 2707 incident prostate cancer cases were diagnosed and categorized as low-, intermediate-, or high-risk, based on disease grade and stage. Accelerated failure-time models assessed time to diagnosis of prostate cancer. Cox proportional hazard models estimated hazard ratios (HR) and 95% confidence intervals (95% CI). Nonlinear effects of E-DII were modeled as third-order polynomials. RESULTS: Time to prostate cancer diagnosis did not differ by E-DII quartile. The HR for high-risk prostate cancer increased in the third E-DII quartile (HR CONCLUSIONS: Relationships between proinflammatory diet and prostate cancer risk may be nonlinear, with an increased risk above an E-DII threshold of ≈+2.5.

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 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.

8 Article Inflammatory potential of diet and risk of pancreatic cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. 2018

Zheng, Jiali / Merchant, Anwar T / Wirth, Michael D / Zhang, Jiajia / Antwi, Samuel O / Shoaibi, Azza / Shivappa, Nitin / Stolzenberg-Solomon, Rachael Z / Hebert, James R / Steck, Susan E. ·Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC. · Cancer Prevention and Control Program, University of South Carolina, Columbia, SC. · Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX. · Connecting Health Innovations, LLC, Columbia, SC. · Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Jacksonville, FL. · Biomedical Informatics Center, Medical University of South Carolina, Charleston, SC. · Division of Cancer Epidemiology and Genetics, Metabolic Epidemiology Branch, National Cancer Institute (NCI/DCEG), Rockville, MD. ·Int J Cancer · Pubmed #29355939.

ABSTRACT: Inflammation plays a central role in pancreatic cancer etiology and can be modulated by diet. We aimed to examine the association between the inflammatory potential of diet, assessed with the Dietary Inflammatory Index (DII®), and pancreatic cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial prospective cohort. Our study included 101,449 participants aged 52-78 years at baseline who completed both baseline questionnaire and a diet history questionnaire. Energy-adjusted DII (E-DII) scores were computed based on food and supplement intake. Cox proportional hazards models and time dependent Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with participants in the lowest E-DII quintile (most anti-inflammatory scores) as referent. After a median 8.5 years of follow-up, 328 pancreatic cancer cases were identified. E-DII scores were not associated with pancreatic cancer risk in the multivariable model (HR

9 Article HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer. 2017

Stojanovic, N / Hassan, Z / Wirth, M / Wenzel, P / Beyer, M / Schäfer, C / Brand, P / Kroemer, A / Stauber, R H / Schmid, R M / Arlt, A / Sellmer, A / Mahboobi, S / Rad, R / Reichert, M / Saur, D / Krämer, O H / Schneider, G. ·II. Medizinische Klinik, Technische Universität München, München, Germany. · Department of Toxicology, University of Mainz Medical Center, Mainz, Germany. · Institute of Biochemistry and Biophysics/Center for Molecular Biomedicine (CMB), Friedrich-Schiller-University Jena, Jena, Germany. · Molecular and Cellular Oncology/ENT, University Medical Center Mainz, Mainz, Germany. · Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute of Pharmacy, Department of Pharmaceutical Chemistry I, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ·Oncogene · Pubmed #27721407.

ABSTRACT: Mutation of p53 is a frequent genetic lesion in pancreatic cancer being an unmet clinical challenge. Mutants of p53 have lost the tumour-suppressive functions of wild type p53. In addition, p53 mutants exert tumour-promoting functions, qualifying them as important therapeutic targets. Here, we show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine pancreatic cancer cells. Our data reveal that the inhibition of these HDACs with small molecule HDAC inhibitors (HDACi), as well as the specific genetic elimination of HDAC1 and HDAC2, reduce the expression of mutant p53 mRNA and protein levels. We further show that HDAC1, HDAC2 and MYC directly bind to the TP53 gene and that MYC recruitment drops upon HDAC inhibitor treatment. Therefore, our results illustrate a previously unrecognized class I HDAC-dependent control of the TP53 gene and provide evidence for a contribution of MYC. A combined approach targeting HDAC1/HDAC2 and MYC may present a novel and molecularly defined strategy to target mutant p53 in pancreatic cancer.

10 Article MYC: A Stratification Marker for Pancreatic Cancer Therapy. 2016

Wirth, Matthias / Schneider, Günter. ·II. Medizinische Klinik, Technische Universität München, München, 81675, Germany. · II. Medizinische Klinik, Technische Universität München, München, 81675, Germany. Electronic address: guenter.schneider@tum.de. ·Trends Cancer · Pubmed #28741497.

ABSTRACT: One approach to improve cancer treatment is to stratify patients and to develop subgroup-specific therapies. We will discuss the potential of MYC as a stratification marker in pancreatic ductal adenocarcinoma. Furthermore, we will point to possibilities for how to annotate the MYC status and how to target MYC-associated vulnerabilities.

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 Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells. 2016

Diersch, S / Wirth, M / Schneeweis, C / Jörs, S / Geisler, F / Siveke, J T / Rad, R / Schmid, R M / Saur, D / Rustgi, A K / Reichert, M / Schneider, G. ·II. Medizinische Klinik, Technische Universität München, München, Germany. · Division of Translational Solid Tumor Oncology, German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 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, Philadelphia, PA, USA. ·Oncogene · Pubmed #26592448.

ABSTRACT: Epidermal growth factor receptor (EGFR) signaling has a critical role in oncogenic Kras-driven pancreatic carcinogenesis. However, the downstream targets of this signaling network are largely unknown. We developed a novel model system utilizing murine primary pancreatic ductal epithelial cells (PDECs), genetically engineered to allow time-specific expression of oncogenic Kras(G12D) from the endogenous promoter. We show that primary PDECs are susceptible to Kras(G12D)-driven transformation and form pancreatic ductal adenocarcinomas in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of Kras(G12D) induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease Kras(G12D)-activated ERK or PI3K signaling. Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC. EGFR and c-MYC have been shown to be essential for pancreatic carcinogenesis. Importantly, our data link both pathways and thereby explain the crucial role of EGFR for Kras(G12D)-driven carcinogenesis in the pancreas.

13 Article Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. 2015

Mazur, Pawel K / Herner, Alexander / Mello, Stephano S / Wirth, Matthias / Hausmann, Simone / Sánchez-Rivera, Francisco J / Lofgren, Shane M / Kuschma, Timo / Hahn, Stephan A / Vangala, Deepak / Trajkovic-Arsic, Marija / Gupta, Aayush / Heid, Irina / Noël, Peter B / Braren, Rickmer / Erkan, Mert / Kleeff, Jörg / Sipos, Bence / Sayles, Leanne C / Heikenwalder, Mathias / Heßmann, Elisabeth / Ellenrieder, Volker / Esposito, Irene / Jacks, Tyler / Bradner, James E / Khatri, Purvesh / Sweet-Cordero, E Alejandro / Attardi, Laura D / Schmid, Roland M / Schneider, Guenter / Sage, Julien / Siveke, Jens T. ·Department of Pediatrics, Stanford University School of Medicine, California, USA. · Department of Genetics, Stanford University School of Medicine, California, USA. · Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Radiation Oncology, Stanford University School of Medicine, California, USA. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · David H. Koch Institute for Integrative Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. · Department of Medicine, Stanford University School of Medicine, California, USA. · Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, California, USA. · Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany. · Ruhr-University Bochum, Medical Clinic, Knappschaftskrankenhaus, Bochum, Germany. · Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Institute of Pathology, University of Tübingen, Tübingen, Germany. · Institute of Virology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Division of Chronic Inflammation and Cancer, German Cancer Research center (DKFZ) Heidelberg, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany. · Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. ·Nat Med · Pubmed #26390243.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.

14 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.

15 Article A simple and cost-effective method to transfect small interfering RNAs into pancreatic cancer cell lines using polyethylenimine. 2011

Wirth, Matthias / Fritsche, Petra / Stojanovic, Natasa / Brandl, Martina / Jaeckel, Stephanie / Schmid, Roland M / Saur, Dieter / Schneider, Günter. ·Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, München, Germany. ·Pancreas · Pubmed #20938367.

ABSTRACT: OBJECTIVES: RNA interference, an indispensable tool in functional genomics, can be induced by small interfering RNAs (siRNAs). Because of the transient nature of siRNA-mediated RNA interference, the continuous use of transfection reagents is mandatory. Because transfection reagents are expensive, cost-effective alternatives must be considered. In this study, we describe a polyethylenimine-based siRNA transfection protocol for pancreatic cancer cell lines. METHODS: For determination of polyethylenimine-based transfection efficiency, a FAM-labeled siRNA was transfected into several pancreatic cancer cell lines and subsequently analyzed by flow cytometry. The effective knockdown of 2 siRNAs was determined on the protein level by Western blot. Toxicity of the transfection reagent was analyzed by viability assays. RESULTS: Polyethylenimine can be used without overt cellular morphological changes, and toxicity is negligible in human and murine pancreatic cancer cell lines. Transfection efficiencies ranged between 83% and 98% in the cell lines used. The knockdown at the protein level was comparable to commercially available transfection reagents. Polyethylenimine and siRNA concentrations, incubation time, and cell density are determinates of the transfection efficiency. CONCLUSIONS: Polyethylenimine is a suitable and cost-effective alternative for transfecting siRNAs into pancreatic cancer cells.