Mouse models for pancreatic ductal adenocarcinoma are affected by the cre-driver used to promote KRASG12D activation.

Abstract

Background and aims: The fundamental biology of pancreatic ductal adenocarcinoma has been greatly impacted by the characterization of genetically engineered mouse models that allow temporal and spatial activation of oncogenic KRAS (KRAS^G12D). One of the most commonly used models involves targeted insertion of a cre-recombinase into the Ptf1a gene. However, this approach disrupts the Ptf1a gene, resulting in haploinsufficiency that likely affects sensitivity to oncogenic KRAS (KRAS^G12D). This study aims to determine if Ptf1a haploinsufficiency affected the acinar cell response to KRAS^G12D before and after induction of pancreatic injury.

Methods: We performed morphological and molecular analysis of three genetically engineered mouse models that express a tamoxifen-inducible cre-recombinase to activate Kras^G12D in acinar cells of the pancreas. The cre-recombinase was targeted to the acinar-specific transcription factor genes, Ptf1a or Mist1/Bhlha15, or expressed within a BAC-derived Elastase transgene. Histological and RNA-seq analyses were used to delineate differences between the models.

Results: Up to two months after tamoxifen induction of KRAS^G12D, morphological changes were negligible. However, induction of pancreatic injury by cerulein resulted in widespread PanIN lesions in Ptf1a^creERT pancreata within seven days and maintained for at least five weeks post-injury, which was not seen in the models with two functional Ptf1a alleles. RNA-seq analysis prior to injury induction suggested Ptf1a^creERT and Mist1^creERT mice have unique profiles of gene expression that predict a differential response to injury. Multiplex analysis of pancreatic tissue confirmed different inflammatory responses between the models.

Conclusions: These findings suggest Ptf1a haploinsufficiency in Ptf1a^creERT mouse models promotes KRAS^G12D priming of genes for promotion of PDAC.