Abstract
Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Recent multi-gene analysis approaches such as next-generation sequencing have provided useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic cancer and precursor lesions are characterized by specific molecular alterations. Genetically engineered mouse models (GEMMs) of PDAC are useful tools to understand the roles of altered genes. Most GEMMs are driven by oncogenic Kras, and can recapitulate the histological and molecular hallmarks of human PDAC and comparable precursor lesions. In this review, we summarize the main molecular alterations found in pancreatic neoplasms and GEMMs developed based on these alterations.Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, and the seventh leading cause of cancer-related deaths worldwide. An improved understanding of tumor biology and novel therapeutic discoveries are needed to improve overall survival. Recent multi-gene analysis approaches such as next-generation sequencing have provided useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic cancer and precursor lesions are characterized by specific molecular alterations. Genetically engineered mouse models (GEMMs) of PDAC are useful to understand the roles of altered genes. Most GEMMs are driven by oncogenic Kras, and can recapitulate the histological and molecular hallmarks of human PDAC and comparable precursor lesions. Advanced GEMMs permit the temporally and spatially controlled manipulation of multiple target genes using a dual-recombinase system or CRISPR/Cas9 gene editing. GEMMs that express fluorescent proteins allow cell lineage tracing to follow tumor growth and metastasis to understand the contribution of different cell types in cancer progression. GEMMs are widely used for therapeutic optimization. In this review, we summarize the main molecular alterations found in pancreatic neoplasms, developed GEMMs, and the contribution of GEMMs to the current understanding of PDAC pathobiology. Furthermore, we attempted to modify the categorization of altered driver genes according to the most updated findings.
Highlights
Pancreatic cancer is one of the most lethal cancers, with a rising incidence, in developed countries
These Pik3ca mutant pancreatic cancers were shown to be morphologically indistinguishable from Kras mutant models, demonstrating the importance of PI3K signaling in the oncogenic potential of pancreatic cancer
These results indicate that the RAF/MEK/ERK and PI3K/AKT signaling pathways play a central role in the initiation and development of Pancreatic ductal adenocarcinoma (PDAC)
Summary
Pancreatic cancer is one of the most lethal cancers, with a rising incidence, in developed countries. PDAC is genetically homogeneous with recurrent mutations in four genes. The authors demonstrated that molecular subtypes are linked to specific copy number aberrations in genes such as mutant KRAS and GATA6, and disease heterogeneity is due to ongoing genomic instability during progression [8]. Five precursor lesions of PDAC have been recognized: pancreatic intraepithelial neoplasia (PanIN) [9], intraductal papillary mucinous neoplasm (IPMN) [10], intraductal oncocytic papillary neoplasm (IOPN) [11], pancreatic intraductal tubulopapillary neoplasm (ITPN) [12], and mucinous cystic neoplasm (MCN) [13]. IOPN is classically considered as one of the subtypes of IPMN It is recognized as a distinct entity [14].
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