Establishment of a pancreatic cancer animal model using the pancreas-targeted hydrodynamic gene delivery method

• Published in: Molecular therapy. Nucleic acids 2022-06, Vol.28, p.342-352
• Main Authors: Shibata, Osamu, Kamimura, Kenya, Tanaka, Yuto, Ogawa, Kohei, Owaki, Takashi, Oda, Chiyumi, Morita, Shinichi, Kimura, Atsushi, Abe, Hiroyuki, Ikarashi, Satoshi, Hayashi, Kazunao, Yokoo, Takeshi, Terai, Shuji
• Format: Article
• Language: English
• Subjects: animal model; delivery strategies; gene delivery; hydrodynamic gene delivery; MT: Delivery Strategies; oncogene; Original; pancreatic cancer
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2022.03.019

This research developed an easy-to-use, reproducible pancreatic cancer animal model utilizing pancreas-targeted hydrodynamic gene delivery to deliver human pancreatic cancer-related genes to the pancreas of wild-type rats. KRASG12D-induced pancreatic intraepithelial neoplasia lesions showed malignant transformation in the main pancreatic duct at 4 weeks and developed acinar-to-ductal metaplasia, which led to pancreatic ductal adenocarcinoma within 5 weeks, and the gene combination of KRASG12D and YAP enhanced these effects. The repeat hydrodynamic gene delivery of KRASG12D + YAP combination at 4 weeks showed acinar-to-ductal metaplasia in all rats and pancreatic ductal adenocarcinoma in 80% of rats 1 week later. Metastatic tumors in the liver, lymph nodes, and subcutaneous lesions and nervous invasion were confirmed. KRASG12D and YAP combined transfer contributes to the E- to N-cadherin switch in pancreatic ductal adenocarcinoma cells and to tumor metastases. This pancreatic cancer model will speed up pancreatic cancer research for novel treatments and biomarkers for early diagnosis. [Display omitted] In this study, Kamimura and colleagues describe pancreas-targeted hydrodynamic gene delivery of human pancreatic cancer-related genes to develop an easy-to-use, reproducible animal model of pancreatic cancer in wild-type rats. This pancreatic cancer model will facilitate pancreatic cancer research for the development of novel effective therapies and biomarkers for early diagnosis.