Mouse Models for Pancreatic Ductal Adenocarcinoma are Affected by the cre-driver Used to Promote KRASG12D Activation
Fatemeh Mousavi1, Joyce Thompson2, Justine Lau1
1Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
Background & 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 (KRASG12D). 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 (KRASG12D). This study aims to determine if Ptf1a haploinsufficiency affected the acinar cell response to KRASG12D before and after induction of pancreatic injury.
Methods:
We performed morphological and molecular analysis of 3 genetically engineered mouse models that express a tamoxifen-inducible cre-recombinase to activate KrasG12D 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 2 months after tamoxifen induction of KRASG12D, morphological changes were negligible. However, induction of pancreatic injury by cerulein resulted in widespread PanIN lesions in Ptf1acreERT pancreata within 7 days and maintained for at least 5 weeks post-injury, which was not seen in the models with 2 functional Ptf1a alleles. RNA-sequencing analysis prior to injury induction suggested Ptf1acreERT and Mist1creERT 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 Ptf1acreERT mouse models promotes KRASG12D priming of genes for promotion of pancreatic ductal adenocarcinoma.
Insights
Ptf1a haploinsufficiency in mouse models accelerates pancreatic ductal adenocarcinoma development by priming genes for KRAS G12D. This finding impacts the understanding of pancreatic cancer biology and therapeutic strategies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Genetically engineered mouse models are crucial for studying pancreatic ductal adenocarcinoma (PDAC) biology.
- Activating oncogenic KRAS (KRASG12D) is a key event in PDAC development.
- Commonly used models targeting Ptf1a disrupt the gene, causing haploinsufficiency that may influence PDAC progression.
Purpose of the Study:
- To investigate the impact of Ptf1a haploinsufficiency on acinar cell response to KRASG12D.
- To determine if Ptf1a haploinsufficiency affects PDAC development before and after pancreatic injury.
Main Methods:
- Utilized three genetically engineered mouse models with tamoxifen-inducible cre-recombinase to activate KRASG12D in pancreatic acinar cells.
- Targeted cre-recombinase to Ptf1a, Mist1/Bhlha15, or used an Elastase transgene.
- Conducted histological and RNA-sequencing analyses to compare models.
Main Results:
- KRASG12D induction alone showed negligible morphological changes up to 2 months.
- Cerulein-induced pancreatic injury led to widespread PanIN lesions in Ptf1acreERT mice, unlike controls.
- RNA-seq and multiplex analyses revealed distinct gene expression profiles and inflammatory responses between models, predicting differential injury responses.
Conclusions:
- Ptf1a haploinsufficiency in Ptf1acreERT models promotes KRASG12D-driven gene expression.
- This gene priming facilitates the development of pancreatic ductal adenocarcinoma.
- Findings highlight the importance of Ptf1a in PDAC pathogenesis.
