Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors.

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 bitransgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in b-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. The utility of this model is enhanced by ability to form tumor-derived allografts. 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. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics. All animal work was performed in accordance with the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals under UTSW and UAB Institutional Animal Care and Use Committee approved protocols. Bi-transgenic Ins-p25OE animals were generated from crossing of the tetOp-p25GFP strain (The Jackson Laboratory stock # 005706) with the Ins2-rtTA strain (The Jackson Laboratory stock # 008250). Breeders and pups were maintained in the absence of doxycycline to allow for normal development of offspring prior to transgene induction. Upon weaning, at 3-4 weeks of age, offspring were administered 1 mg/L doxycycline via drinking water to induce transgene expression in bi-transgenic animals. Bi-transgenic animals were co-housed with transgene negative littermates. Transgene negative littermates were used as normal controls. All mice were maintained in the C57BL/6 background. Animals were euthanized by CO2 administration and cardiac perfusion.