Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease. Surgical resection of the primary tumor is the only treatment that offers a perspective for prolonged survival. However, the majority of patients with resectable disease experience recurrence within 2 years, pointing at an urgent need for development of more effective (neo-)adjuvant treatment strategies.
The availability of clinically relevant mouse models can contribute to this goal. Unfortunately, the currently available models have significant limitations. In brief, transplantable models do not recapitulate the fibrotic tumor microenvironment of PDAC, while in genetically engineered orthotopic models the entire pancreas is transformed into a premalignant lesion containing small PDAC tumor cell areas.
We have developed an autochthonous PDAC mouse model in which in vivo electroporation of gene constructs into the pancreas results in a single, focal tumor. By using a transposon encoding mutated K-ras in combination with CRISPR/cas9 genome editing using guide RNAs targeting the p53 tumor suppressor gene, we can induce PDAC tumors with >90% efficiency in regular B6 mice. This allows for induction of PDAC tumors in transgenic or ko-strains of interest, and for generating genetic tumor variants by including further guide RNAs.
We found that combination regimens including immunostimulatory antibodies, selected on basis of their efficacy in transplantable PDA models, are also effective in our autochthonous, electroporation-based model. Since this model offers the possibility of primary tumor resection, we are now proceeding with testing immunotherapeutic interventions in the (neo-) adjuvant setting.