Related Experiment Video
Updated: May 16, 2026
A Preclinical Murine Model of Hepatic Metastases
Published on: September 27, 2014
Metastatic pancreatic cancer is dependent on oncogenic Kras in mice
Meredith A Collins1, Jean-Christophe Brisset, Yaqing Zhang
1Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, United States of America.
Abstract:
Pancreatic cancer is one of the deadliest human malignancies, and its prognosis has not improved over the past 40 years. Mouse models that spontaneously develop pancreatic adenocarcinoma and mimic the progression of the human disease are emerging as a new tool to investigate the basic biology of this disease and identify potential therapeutic targets. Here, we describe a new model of metastatic pancreatic adenocarcinoma based on pancreas-specific, inducible and reversible expression of an oncogenic form of Kras, together with pancreas-specific expression of a mutant form of the tumor suppressor p53. Using high-resolution magnetic resonance imaging to follow individual animals in longitudinal studies, we show that both primary and metastatic lesions depend on continuous Kras activity for their maintenance. However, re-activation of Kras* following prolonged inactivation leads to rapid tumor relapse, raising the concern that Kras*-resistance might eventually be acquired. Thus, our data identifies Kras* as a key oncogene in pancreatic cancer maintenance, but raises the possibility of acquired resistance should Kras inhibitors become available for use in pancreatic cancer.
Insights
New mouse models reveal Kras oncogene dependence in pancreatic cancer. Continuous Kras activity is crucial for tumor maintenance, but resistance may develop upon reactivation, impacting future therapies.
Area of Science:
- Oncology
- Genetics
- Animal Models
Background:
- Pancreatic cancer remains a highly lethal malignancy with stagnant survival rates.
- Novel mouse models are critical for understanding pancreatic adenocarcinoma and identifying therapeutic targets.
Purpose of the Study:
- To develop and characterize a new inducible and reversible mouse model of metastatic pancreatic adenocarcinoma.
- To investigate the role of Kras oncogene activity in the maintenance of pancreatic tumors and metastases.
Main Methods:
- Generated a mouse model with pancreas-specific, inducible Kras and mutant p53 expression.
- Utilized high-resolution magnetic resonance imaging for longitudinal tracking of primary and metastatic lesions.
- Assessed tumor response to Kras inactivation and subsequent reactivation.
Main Results:
- Primary and metastatic pancreatic tumors require continuous Kras activity for maintenance.
- Inactivation of Kras leads to tumor regression, but rapid relapse occurs upon reactivation.
- The findings suggest a potential for acquired resistance to Kras-targeted therapies.
Conclusions:
- Kras is a key oncogene for pancreatic cancer maintenance in this model.
- The reversibility of Kras activity highlights potential challenges with acquired resistance to Kras inhibitors.
- This model provides a valuable platform for studying pancreatic cancer biology and therapeutic strategies.
