Research Fellow, Mayo Clinic
Developing Novel KC Pre-Clinical Models for Pancreatic Cancer Research
Overview
Aim: Basic Science
Pancreatic ductal adenocarcinoma (PDAC) research heavily depends on genetically engineered pre-clinical models to study tumor initiation and evaluate novel therapies. While the widely used KC models (LSL-KrasG12D/+; Pdx1-Cre or p48-Cre) have substantially advanced our understanding of PDAC, they are hindered by several critical limitations. In LSL-KrasG12D/+ mice, wild-type (WT) Kras expression is disrupted in all cells, the resulting heterozygous loss of WT Kras in the immune system may confound tumor progression and therapeutic response assessments. Moreover, the use of pancreas specific-Cre to generate pancreas specific knock-out models, Pdx1-Cre exhibits off-target recombination in nonpancreatic tissues such as the liver, complicating interpretation of metastasis and systemic effects. Although p48-Cre is more pancreas-specific, it disrupts the endogenous p48 expression, impairing pancreatic development and tumor progression; homozygosity results in embryonic lethality.
These limitations collectively reduce physiological relevance, compromise model fidelity, lower breeding efficiency, and increase animal usage and housing costs. To address these challenges, we propose to develop a next-generation KC model that retains both WT Kras alleles prior to Cre recombination and enables physiological expression of mutant Kras via Cre-mediated inversion. Additionally, we will engineer a pancreas-specific p48-IRES-Cre driver that does not interfere with endogenous p48 expression. This refined system will improve the accuracy of disease modeling, eliminate off-target effects, streamline breeding strategies, and reduce animal use, providing a valuable tool not only for PDAC research but also for investigating Kras-driven pathologies in other organ systems.
