Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. This study demonstrates that the combination of KrasG12D activation and Ink4a/Arf deletion in mice leads to the development of highly invasive and metastatic pancreatic ductal adenocarcinoma. KrasG12D alone causes premalignant ductal lesions, while Ink4a/Arf deletion alone does not. However, together, they result in rapid progression to invasive and metastatic cancers. The tumors in mice closely resemble human pancreatic adenocarcinoma, with proliferative stromal components and ductal lesions that progress to poorly differentiated states. These findings support the model in which activated KRAS initiates PanIN lesions, and INK4A/ARF functions to constrain malignant conversion. The mouse model provides a platform for studying genetic lesions in human pancreatic cancer and for identifying early disease markers and testing novel therapies. The study highlights the role of Ink4a/Arf in restraining malignant progression, with INK4A/ARF loss contributing to the progression of PanIN lesions to invasive cancer. The results suggest that the cooperative interactions between Kras activation and Ink4a/Arf deficiency are critical in the development of pancreatic ductal adenocarcinoma. The mouse model recapitulates key features of human pancreatic adenocarcinoma, including invasion, metastasis, and the presence of stromal components. The study also shows that the loss of Ink4a/Arf allows for the progression of PanIN lesions to invasive cancer, indicating that INK4A/ARF functions to restrain malignant transformation. The findings provide important insights into the genetic and molecular mechanisms underlying pancreatic ductal adenocarcinoma and highlight the importance of the Ink4a/Arf locus in tumor suppression. The study underscores the need for further research into the genetic and molecular pathways involved in pancreatic cancer development and progression.Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. This study demonstrates that the combination of KrasG12D activation and Ink4a/Arf deletion in mice leads to the development of highly invasive and metastatic pancreatic ductal adenocarcinoma. KrasG12D alone causes premalignant ductal lesions, while Ink4a/Arf deletion alone does not. However, together, they result in rapid progression to invasive and metastatic cancers. The tumors in mice closely resemble human pancreatic adenocarcinoma, with proliferative stromal components and ductal lesions that progress to poorly differentiated states. These findings support the model in which activated KRAS initiates PanIN lesions, and INK4A/ARF functions to constrain malignant conversion. The mouse model provides a platform for studying genetic lesions in human pancreatic cancer and for identifying early disease markers and testing novel therapies. The study highlights the role of Ink4a/Arf in restraining malignant progression, with INK4A/ARF loss contributing to the progression of PanIN lesions to invasive cancer. The results suggest that the cooperative interactions between Kras activation and Ink4a/Arf deficiency are critical in the development of pancreatic ductal adenocarcinoma. The mouse model recapitulates key features of human pancreatic adenocarcinoma, including invasion, metastasis, and the presence of stromal components. The study also shows that the loss of Ink4a/Arf allows for the progression of PanIN lesions to invasive cancer, indicating that INK4A/ARF functions to restrain malignant transformation. The findings provide important insights into the genetic and molecular mechanisms underlying pancreatic ductal adenocarcinoma and highlight the importance of the Ink4a/Arf locus in tumor suppression. The study underscores the need for further research into the genetic and molecular pathways involved in pancreatic cancer development and progression.