Characterization of pancreatic glucagon-producing tumors and pituitary gland tumors in transgenic mice overexpressingMYCNinhGFAP-positive cells

// Kathrin Fielitz 1 , Kristina Althoff 1 , Katleen De Preter 2 , Julie Nonnekens 3 , Jasmin Ohli 4 , Sandra Elges 5 , Wolfgang Hartmann 5 , Günter Klöppel 6 , Thomas Knösel 7 , Marc Schulte 1 , Ludger Klein-Hitpass 8 , Daniela Beisser 9 , Henning Reis 10 , Annette Eyking 11 , Elke Cario 11 , Johannes H. Schulte 12 , Alexander Schramm 1,* and Ulrich Schüller 4,13,14,15,* 1 Department of Pediatric Oncology and Hematology, University Children’s Hospital Essen, University of Duisburg-Essen, Essen, Germany 2 Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium 3 Genetics and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands 4 Center for Neuropathology, Ludwig-Maximilians University, Munich, Germany 5 Department of Pathology, University Hospital, Münster, Germany 6 Department of Pathology, Technical University, Munich, Germany 7 Department of Pathology, Ludwig-Maximilians University, Munich, Germany 8 Cell Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 9 Genome Informatics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 10 Department of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 11 Division of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 12 Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany 13 Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany 14 Research Institute Childrens Cancer Center, Hamburg, Germany 15 Department of Pediatric Oncology and Hematology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany * These authors have contributed equally to this work Correspondence to: Alexander Schramm, email: // Keywords : glucagonoma; pancreatic neuroendocrine tumors; MYCN Received : June 04, 2016 Accepted : October 13, 2016 Published : October 19, 2016 Abstract Amplification or overexpression of MYCN is involved in development and maintenance of multiple malignancies. A subset of these tumors originates from neural precursors, including the most aggressive forms of the childhood tumors, neuroblastoma and medulloblastoma. In order to model the spectrum of MYCN -driven neoplasms in mice, we transgenically overexpressed MYCN under the control of the human GFAP-promoter that, among other targets, drives expression in neural progenitor cells. However, LSL-MYCN;hGFAP-Cre double transgenic mice did neither develop neural crest tumors nor tumors of the central nervous system, but presented with neuroendocrine tumors of the pancreas and, less frequently, the pituitary gland. Pituitary tumors expressed chromogranin A and closely resembled human pituitary adenomas. Pancreatic tumors strongly produced and secreted glucagon, suggesting that they derived from glucagon- and GFAP-positive islet cells. Interestingly, 3 out of 9 human pancreatic neuroendocrine tumors expressed MYCN, supporting the similarity of the mouse tumors to the human system. Serial transplantations of mouse tumor cells into immunocompromised mice confirmed their fully transformed phenotype. MYCN-directed treatment by AuroraA- or Brd4-inhibitors resulted in significantly decreased cell proliferation in vitro and reduced tumor growth in vivo . In summary, we provide a novel mouse model for neuroendocrine tumors of the pancreas and pituitary gland that is dependent on MYCN expression and that may help to evaluate MYCN-directed therapies.