Recent evidence has provided an understanding of the molecular mechanisms and genetic changes underlying pancreatic ductal adenocarcinoma (PDAC) pathogenesis; however, limited information is available on progression in the disease. Studies in several genetically engineered mouse models for PDAC suggest that acinar cells, centroacinar cells, and/or postulated stem cells can be responsible for the development of PDAC. This is believed to occur via a process termed ?acinar-to-ductal metaplasia? (ADM), during which a differentiated cell type (acinar) is reversibly replaced with another mature, differentiated cell type, a condition also visible during inflammation, thereby underlining the predisposition of chronic pancreatitis patients to PDAC. Pancreatic differentiation 2 (PD2), also known as polymerase associated factor-1 (Paf1), has been found to be overexpressed in PDAC and to exhibit oncogenic potential. Our previous studies have further defined the role of PD2/Paf1 in cell cycle regulation and in inducing chromatin structure remodeling in PDAC cells. We have also demonstrated that PD2/Paf1 plays a major role in the multi-lineage differentiation of mouse embryonic stem cells and maintains pancreatic cancer stem cells (PCSCs). Our preliminary efforts to investigate the expression of PD2/Paf1 in KrasG12D;Pdx1Cre mouse model of PDAC showed that it is differentially overexpressed in neoplastic pancreatic ducts during murine PDAC progression, as compared to its strictly acinar expression in normal pancreas. PD2/Paf1 was specifically expressed in `intermediate structures' expressing both acinar and ductal specific markers, representing `transitional cells' during pancreatic acinar to ductal metaplasia. Further, we found that PD2/Paf1 is overexpressed along with PCSCs markers in PDAC progression in mouse tissues and isolated CSCs. The multi-potent property of these CSCs allows them to differentiate into several cell types. Therefore, the overall goal of this study is to define the role of PD2/Paf1 in trans-differentiation of acinar cells to ductal cells during PDAC progression, through lineage- differentiation of pancreatic CSC population. Based on these observations our central hypothesis is that ?PD2/Paf1 plays a significant role in the process of acinar-to-ductal metaplasia, thereby contributing to PDAC progression, and its overexpression contributes to the ductal lineage-differentiation of pancreatic CSCs.? To test this hypothesis, Aim 1 will focus on investigating the potential link of PD2/Paf1 in acinar-to-ductal metaplasia using cerulein-induced mouse model of PDAC progression.
Aim 2 will elucidate the mechanism(s) of PD2/Paf1 in acinar-to-ductal metaplasia using acinar cells, organoid 3D-cultures, and PD2-/- animals.
In Aim 3, we will understand the functional mechanism of PD2/Paf1 in ductal lineage-differentiation of pancreatic CSCs in PDAC progression. Taken together, understanding of novel roles of PD2/Paf1 in ADM progression through stem-like cell differentiation will lead to critical information for the long-term goal of developing novel, targeted therapy against PDAC.
Although knowledge has been gained on the molecular mechanisms and genetic changes underlying pancreatic cancer pathogenesis, very little light has been shed on the origin of this disease. The current proposal seeks to investigate the primary goal of our proposal is to investigate the multi-functional role of pancreatic differentiation 2 (PD2) or polymerase associated factor-1 (Paf1) in acinar to ductal metaplasia and cancer stem cell maintenance during pancreatic cancer development. The impact of the application is determining novel roles of PD2/Paf1 in ADM initiation and ductal lineage-differentiation of pancreatic CSCs would provide critical information for the long-term goal of developing novel targeted therapy against pancreatic cancer.
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