Abstract
Pancreatic cancer is often treatment-resistant, with the emerging standard of care, gemcitabine, affording only a few months of incrementally-deteriorating survival. Reflecting on the history of failed clinical trials, genetically engineered mouse models (GEMMs) in oncology research provides the inspiration to discover new treatments for pancreatic cancer that come from better knowledge of pathogenesis mechanisms, not only of the derangements in and consequently acquired capabilities of the cancer cells, but also in the aberrant microenvironment that becomes established to support, sustain, and enhance neoplastic progression. On the other hand, the existing mutational profile of pancreatic cancer guides our understanding of the disease, but leaves many important questions of pancreatic cancer biology unanswered. Over the past decade, a series of transgenic and gene knockout mouse modes have been produced that develop pancreatic cancers with features reflective of metastatic pancreatic ductal adenocarcinoma (PDAC) in humans. Animal models of PDAC are likely to be essential to understanding the genetics and biology of the disease and may provide the foundation for advances in early diagnosis and treatment.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most deadly of common human adult malignancies [1]
We demonstrated that key effectors of TG-interacting factor 1 (TGIF1) loss in murine pancreatic ductal adenocarcinoma (PDAC) biology and determined that TGIF1 loss led to more aggressive immune suppression, epithelial-to-mesenchymal transition (EMT)-high, and elevated stemness gene signature phenotypes of
We showed that loss of KLF10 cooperates with KrasG12D leading to an invasive and widely metastatic phenotype of PDAC
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most deadly of common human adult malignancies [1]. In the context of PDAC pathogenesis, it should be important to determine what signals, if any, provoke INK4A and ARF expression in PanIN of various stages, and to identify specific roles of either gene in restraining PanIN progression In this model, LSL-KrasG12D, Pdx1-Cre, Ink4a/ArfLoxp/Loxp mice with documented efficient deletion of the Ink4a/Arf in the pancreas developed weight loss, ascites, jaundice, and a palpable abdominal mass between seven and 11 weeks of age [7]. The tumors were highly invasive, frequently involving the duodenum and/or spleen and occasionally obstructing the common bile duct; gross and microscopic metastases to liver and lung were not evident [7] This phenotypic comparison of the Pdx1-Cre, LSL-KrasG12D mice with the Pdx1-Cre, LSL-KrasG12D, Ink4a/ArfLoxp/Loxp mice unequivocally proves a role of Ink4a/Arf in constraining the malignant progression of early-stage ductal neoplasms
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