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Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors.
Carter, Angela M; Kumar, Nilesh; Herring, Brendon; Tan, Chunfeng; Guenter, Rachael; Telange, Rahul; Howse, Wayne; Viol, Fabrice; McCaw, Tyler R; Bickerton, Hayden H; Gupta, Priyanka; Gillardon, Frank; Woltering, Eugene A; Dhall, Deepti; Totenhagen, John; Banerjee, Ronadip R; Kurian, Elizabeth M; Reddy, Sushanth; Chen, Herbert; Schrader, Joerg; Bart Rose, J; Mukhtar, M Shahid; Bibb, James A.
Afiliación
  • Carter AM; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA. angelamcarter@uabmc.edu.
  • Kumar N; Department of Biology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Herring B; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Tan C; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • Guenter R; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Telange R; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Howse W; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Viol F; Department of Internal Medicine, University Hospital Hamburg-Eppendorf, Hamburg, 20246, Germany.
  • McCaw TR; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Bickerton HH; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Gupta P; UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Gillardon F; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Woltering EA; Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Diseases Research, Birkendorferstrasse 65, 88397, Biberach an der Riss, Germany.
  • Dhall D; Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA.
  • Totenhagen J; Department of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Banerjee RR; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Kurian EM; Department of Medicine, Division of Endocrinology, Diabetees & Metabolism, Johs Hopkins school of Medicine, Baltimore, MD, 21224, USA.
  • Reddy S; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • Chen H; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Schrader J; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Bart Rose J; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Mukhtar MS; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • Bibb JA; Department of Internal Medicine, University Hospital Hamburg-Eppendorf, Hamburg, 20246, Germany.
Oncogenesis ; 10(12): 83, 2021 Dec 03.
Article en En | MEDLINE | ID: mdl-34862365
ABSTRACT
Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in ß-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.