Using mouse models to dissect cellular lineages and the molecular mechanisms of pancreatic cancer
Abstract
Pancreatic cancer is the fourth leading cause of cancer related death in the United States, with pancreatic adenocarcinoma (PDA) representing the majority of human pancreatic cancer cases. A key PDA precursor lesion, termed pancreatic intraepithelial neoplasia (PanIN), has been identified in human PDA samples and PanIN development has been successfully recapitulated in several mouse models. However, the cellular lineages of PanIN/PDA, as well as the signaling and transcription networks that regulate PanIN progression, are not well understood. Previous studies suggested that acinar cells may contribute to pancreatic tumorigenesis through acinar-to-ductal metaplasia (ADM). In this thesis, new genetically engineered mouse lines were generated that expressed Cre recombinase from the Mist1 allele, which normally encodes an acinar-restricted basic helix-loop-helix (bHLH) transcription factor. When KrasG12D expression was induced in an acinar-restricted manner using the Mist1Cre mouse line, the full spectrum of PanIN lesions was observed. Lineage tracing studies showed that these lesions were derived from differentiated acinar cells, suggesting that these cells served as the “cell of origin” for transformation. Next, the role of Mist1 in pancreatic tumorigenesis was evaluated. Loss of Mist1 accelerated Kras-induced PanIN progression through a rapid conversion of normal acinar cells into PanIN lesions. Further analysis indicated that loss of Mist1 led to hyperactivation of the epithelial growth factor receptor (EGFR) pathway, which cooperated with Kras signaling to promote PanIN development. To better understand the molecular mechanisms of ADM formation, a collagen-based 3D cell culture system was established where KrasG12D expression can convert clusters of acinar cells into duct-like cysts. Further analysis revealed that activation of the mitogen-activated protein kinase (MAPK) pathway was essential for this conversion. Interestingly, loss of Mist1 enhanced the generation of ductal cysts, while forced expression of Mist1 in acinar cells greatly reduced ductal cyst formation. Taken together, these data provide definitive proof that acinar cells contribute to pancreatic tumorigenesis via transdifferentiation into ductal-like cells, which can be negatively regulated by Mist1.
Degree
Ph.D.
Advisors
Konieczny, Purdue University.
Subject Area
Genetics
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