The Use of Genetically Engineered Mouse Models for Studying the Function of Mutated Driver Genes in Pancreatic Cancer

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.

DWI Metrics Differentiating Benign Intraductal Papillary Mucinous Neoplasms from Invasive Pancreatic Cancer: A Study in GEM Models

“…The higher level of fibrosis featured by extracellular collagen deposition is shown in CKS tumors ( Figure 4 ). This is consistent with Smad4 deletion, which activates the TGF β pathway downstream, leading to matrix protein deposition [ 4 , 33 ]. We expect the higher extracellular matrix collagen levels in the CKS model to be detected by magnetization transfer techniques, which has been applied to evaluate the extent of fibrosis in tumors and organs such as the liver and kidneys [ 34 , 35 , 36 ].…”

KRAS mutation allele frequency threshold alters prognosis in right‐sided resected pancreatic cancer

“…In transgenic pancreatic cancer mouse models, Kras G12D mutation reliably reproduces human biology with precancerous PanIN lesions in 100% of mice, 10%–20% of which go on to develop PDAC 43 . The inactivation of Tp53 and Smad4 in Kras G12D mice results in 96%–100% of mice developing PDAC 44,45 . In an inducible Kras mutation mouse model, inactivation of mutant Kras resulted in tumor regression and decreased time to metastasis 46 .…”

“…43 The inactivation of Tp53 and Smad4 in Kras G12D mice results in 96%-100% of mice developing PDAC. 44,45 In an inducible Kras mutation mouse model, inactivation of mutant Kras resulted in tumor regression and decreased time to metastasis. 46 Thus, Kras mutation appears to be crucial and sufficient for tumorigenesis and metastasis in PDAC mouse models.…”

Development of thymic tumor in [LSL:KrasG12D;Pdx1-CRE ] mice, an adverse effect associated with accelerated pancreatic carcinogenesis

“…However, this model did not allow to trigger invasive PDAC and was then replaced by several models involving mutated Kras oncogene. KRAS (for Kristen RAS) is a small GTPase of the RAS family having a preponderant role in malignancies, since it is involved in several signaling pathways leading to the activation of cell proliferation [18][19][20] . Single KRAS amino-acid mutation, often on residue G12, results in KRAS constitutive activation and subsequent cell behavior modification.…”